Autosomal dominant calculator: 50% transmission, penetrance, and recurrence risk

Short version. An autosomal dominant condition is caused by a disease allele on an autosome that expresses its phenotype even when present in a single copy. Each child of an affected heterozygous individual has a 50% probability of inheriting the allele. That 50% is the transmission risk, not the disease risk: the disease risk also depends on penetrance (does a carrier manifest?) and expressivity (how severely do they manifest?). A clinically useful autosomal dominant calculator combines the 50% Mendelian transmission with condition-specific penetrance curves, sex-specific and age-specific risks where they apply, and corrections for de novo mutation, germline mosaicism, and the possibility that the apparent dominant pattern is actually pseudodominance or a phenocopy.

What "autosomal dominant" means

In autosomal dominant (AD) inheritance, a single mutant allele on one of the 22 autosomes is sufficient to cause the phenotype. Because the gene is autosomal, both sexes are affected in roughly equal numbers. Because the allele is dominant, a heterozygous individual is affected; a homozygote is usually either severely affected or non-viable, depending on the gene.

At the level of transmission, Mendel's law of segregation gives the simple answer. A heterozygous affected individual produces two kinds of gametes in equal proportion: those carrying the mutant allele and those carrying the wild-type allele. Partnered with an unaffected homozygous individual, each offspring independently has a 50% probability of inheriting the mutation. This does not change with parity: three unaffected children in a row does not reduce the risk for a fourth pregnancy.

Pedigree red flags for a dominant pattern

Before reaching for a calculator, look at the pedigree. A pattern that is autosomal dominant has several recognisable features:

• Vertical transmission: the condition appears in every generation where it is present, passing from parent to child rather than skipping generations.
• Both sexes affected: roughly equal numbers of affected males and females.
• Male-to-male transmission: a single confirmed father-to-son transmission effectively rules out X-linked inheritance. This is a powerful discriminator.
• Affected individuals have at least one affected parent, unless a de novo mutation or non-paternity is in play, or penetrance is reduced.
• Approximately half the offspring of an affected parent are affected, averaged over a reasonable sibship.

These features are soft guides rather than diagnostic rules. Small families, chance clustering, and ascertainment bias can all make a truly AD pattern look ambiguous. The calculator's job is to turn the pedigree into numbers that formalise the intuition.

Reduced penetrance versus variable expressivity

Two concepts are routinely confused and they behave differently in calculations.

Penetrance is the probability that an individual with the disease genotype manifests any recognisable phenotype. Penetrance can be complete (close to 100%), reduced (say, 60-80%), or very low. It can also be age-dependent: Huntington disease has near-zero penetrance in childhood and approaches complete penetrance by about age 70. For an inheritance calculator, reduced penetrance means that a genotype-positive person might be clinically unaffected at the time of assessment, and that transmitted risk can "skip" an apparent generation.

Variable expressivity is the range of severity or presentation among those who do manifest. NF1 is the textbook example: almost every mutation carrier shows some feature, but a carrier may have only cafe-au-lait spots or may have significant plexiform neurofibromas. Expressivity does not change transmission probabilities; it changes the interpretation of "affected" vs "unaffected" on a pedigree and therefore the reliability of your phenotype coding.

For counselling, the practical consequence is this: a 50% transmission probability combined with 80% penetrance gives a 40% risk of manifest disease for each pregnancy. Expressivity does not enter the arithmetic directly but changes how severe the manifest disease is likely to be.

New mutations and recurrence risk

A proportion of cases of several autosomal dominant conditions are not inherited but arise as de novo mutations in the parental germline or early embryo. The clinical implications differ depending on whether the proband's mutation is inherited or de novo.

When the mutation is inherited from an affected parent, recurrence risk for future siblings is 50%. When the mutation is confirmed de novo (the proband is mutation-positive, both parents are mutation-negative on blood testing), recurrence risk for future siblings is low but not zero, because a parent may harbour the variant only in their germline (germline mosaicism). Empirical recurrence-risk estimates vary by condition and by how the germline mosaicism was investigated. Recurrence risk for the proband's own future children returns to 50%.

Conditions with substantial de novo contribution include NF1, achondroplasia, tuberous sclerosis, and Apert syndrome, among others. A Mendelian calculator that ignores the de novo pathway will overestimate sibling recurrence risk for these conditions when the proband appears to be the first affected individual in a family.

Worked examples across the clinical spectrum

A few exemplars illustrate why a single "50%" answer is rarely enough.

HBOC is an instructive special case. The inheritance pattern is autosomal dominant at the gene level — a child of a heterozygous BRCA1 carrier has a 50% probability of inheriting the variant — but the cancer risk for a carrier is sex-dependent (breast and ovarian cancer in females, prostate and breast cancer in males) and strongly age-dependent. For BRCA counselling, the Mendelian 50% is only the first step; empirical models such as BRCAPRO then translate the carrier probability and family history into estimated cancer risks over time. See our hereditary cancer risk assessment guide for the interplay.

Calculating recurrence risk in practice

For a specific pedigree, the calculation typically proceeds in three steps:

1. Establish the likely inheritance pattern. Check the pedigree features listed above. If male-to-male transmission is present, AD or autosomal recessive (pseudodominance) is in play; X-linked is excluded.
2. Calculate prior transmission probabilities. For each unaffected at-risk individual, apply the 50% rule along the chain of inheritance. A grandchild of an obligate carrier is 25% a priori; a great-grandchild is 12.5%.
3. Condition on observed phenotypes using Bayesian updating. An unaffected parent of multiple unaffected children in a highly penetrant dominant pedigree has a reduced residual carrier probability. Observed unaffected offspring "wash out" some of the prior risk; age-dependent penetrance tables give the likelihood terms.

Where molecular testing is available, all of this changes. A confirmed pathogenic variant in the proband converts the calculation from pedigree-based to test-based: family members can be tested directly, and the residual Mendelian uncertainty collapses to the sensitivity and specificity of the assay. Cascade testing of first-degree relatives is often the single most clinically impactful downstream step after identification of a dominant variant.

Common pitfalls

A few traps recur in real consultations:

• Pseudodominance: a pedigree that looks AD may actually be autosomal recessive (AR) if one parent is a carrier and the other is affected. This is most likely with high-frequency AR alleles or in consanguineous families.
• Phenocopies: an unrelated sporadic case mimicking the familial condition can inflate apparent penetrance.
• Ascertainment bias: families come to attention because multiple members are affected, so the observed transmission fraction is biased upwards.
• Small sibships: with three children, observing zero affected still falls within reasonable expectations for a 50% risk; do not over-interpret.
• Non-paternity and adoption: both invalidate the biological pedigree on which the calculation depends and should be considered respectfully where results are surprising.

How Evagene supports this

Evagene's Mendelian inheritance calculator runs autosomal dominant analysis directly on the pedigree as it is drawn. When a condition from the 200+ disease catalogue is annotated on one or more individuals with ICD-10 or OMIM codes, the calculator evaluates whether the observed pattern is consistent with AD, AR, X-linked, or mitochondrial transmission, and assigns per-individual carrier and affected probabilities where data are sufficient. The 50% transmission rule is applied along the pedigree; where condition-specific penetrance and age information are available, those are combined into the residual risk for unaffected at-risk individuals.

For BRCA1 and BRCA2 specifically, Evagene pairs the Mendelian analysis with BRCAPRO, giving both the inheritance-pattern judgement and the BayesMendel carrier and cancer-risk estimates on the same pedigree. Batch risk screening applies the same analysis across the full catalogue for a given proband, surfacing dominant conditions where the family pattern crosses a testing-eligibility threshold even when the clinician has not flagged them explicitly.

AI-assisted interpretation, using your own Anthropic or OpenAI key, then drafts a structured clinical narrative that references the inheritance-pattern findings, penetrance considerations, and data gaps — as a drafting aid, not a substitute for clinical judgement. The pedigree remains the source of truth; the calculator is transparent about which pedigree features drive which numbers.

Frequently asked questions

Related reading

• Mendelian inheritance calculator overview
• Autosomal recessive calculator
• X-linked recessive calculator
• Identifying inheritance patterns from a pedigree
• Carrier probability calculator
• Hereditary cancer risk assessment
• Clinical genetics pedigree tools