Is TMPRSS3 p.Pro322His (c.965C>A) pathogenic?

TMPRSS3 p.Pro322His (c.965C>A) is classified Likely pathogenic in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-12). AlphaMissense: likely pathogenic (0.7846); Absent from gnomAD v4.1; Associated with hearing loss disorder.

What condition is associated with TMPRSS3 p.Pro322His (c.965C>A)?

TMPRSS3 p.Pro322His (c.965C>A) is associated with hearing loss disorder (ClinVar).

How common is TMPRSS3 p.Pro322His (c.965C>A) in the general population?

TMPRSS3 p.Pro322His (c.965C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMPRSS3 p.Pro322His (c.965C>A)?

AlphaMissense predicts likely pathogenic (score 0.7846) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Pro322His

c.965C>A · rs2146430688 · VCV1065053

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7846 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hearing loss disorder

Computational evidence

Protein change
AlphaMissense	0.7846	likely pathogenic ✓ concordant with ClinVar
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -13.79	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 1.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	24.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMPRSS3
Protein: p.Pro322His
Coding: c.965C>A
MANE Select: NM_001256317
dbSNP: rs2146430688
Type: single nucleotide variant
Location: chr21:42380200 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 322: the peptidase s1 domain

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

Disease context

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

Similar variants

TMPRSS3 c.323-6G>A Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Ala138Glu Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Ala306Thr Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Arg106Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
TMPRSS3 p.Trp251Cys Pathogenic ★★ same condition
TMPRSS3 p.Ala359Val Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Asp103Asn Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Gly112Val Uncertain significance ★★ ⚠ same condition

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-pro322his (accessed [today's date]).

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