DIAPH3
Chr 13ADdiaphanous related formin 3
Also known as: AN, AUNA1, DIA2, DRF3, NSDAN, diap3, mDia2
The protein is an actin nucleation and elongation factor that assembles F-actin structures and regulates cytokinesis, stress fiber formation, and transcriptional activation. Mutations cause autosomal dominant auditory neuropathy 1, affecting hearing function through damage to the auditory nerve pathway. The gene shows very low constraint against loss-of-function variants (pLI near zero), suggesting tolerance to such mutations.
Limited evidence — not for standalone diagnostic reporting
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
This gene — mechanism propensity
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
704 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 1 | 0 | 62 | 0 | 63 |
Likely Pathogenic | 0 | 0 | 1 | 0 | 1 |
VUS | 32 | 270 | 47 | 0 | 349 |
Likely Benign | 0 | 9 | 96 | 80 | 185 |
Benign | 0 | 10 | 44 | 7 | 61 |
Conflicting | — | 20 | |||
| Total | 33 | 289 | 250 | 87 | 679 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
DIAPH3 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools