Is TMPRSS3 p.Ala256Val (c.767C>T) pathogenic?

TMPRSS3 p.Ala256Val (c.767C>T) is classified Likely pathogenic in TMPRSS3 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9836); Very rare (popmax 0.00659%, sas); Associated with hearing loss, autosomal recessive.

What condition is associated with TMPRSS3 p.Ala256Val (c.767C>T)?

TMPRSS3 p.Ala256Val (c.767C>T) is associated with hearing loss, autosomal recessive (ClinVar).

How common is TMPRSS3 p.Ala256Val (c.767C>T) in the general population?

TMPRSS3 p.Ala256Val (c.767C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

How is Rare non-syndromic genetic deafness inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TMPRSS3 p.Ala256Val (c.767C>T)?

AlphaMissense predicts likely pathogenic (score 0.9836) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Ala256Val

c.767C>T · rs1306292205 · VCV996723

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hearing loss, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9836	likely pathogenic ✓ concordant with ClinVar · top 8% in TMPRSS3
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -12.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,088 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000372% 6/1,614,142 alleles · very rare exomes 6/1,461,774 · genomes 0/152,368 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TMPRSS3
Protein: p.Ala256Val
Coding: c.767C>T
MANE Select: NM_001256317
dbSNP: rs1306292205
Type: single nucleotide variant
Location: chr21:42383048 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 256: the peptidase s1 domain

Full TMPRSS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hearing loss, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Rare non-syndromic genetic deafness (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

TMPRSS3 c.323-6G>A Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Arg216Cys Pathogenic ★★ same condition
TMPRSS3 p.Arg91Ter Pathogenic ★★ same condition
TMPRSS3 p.Cys406Arg Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Cys194Phe Likely pathogenic ★ same condition
TMPRSS3 c.205+6T>A Uncertain significance ★ same condition
TMPRSS3 c.783-1G>T Pathogenic/Likely pathogenic same condition
TMPRSS3 c.1049-4G>A Likely pathogenic ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tmprss3-p-ala256val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown