Is TMPRSS3 p.Pro403Ala (c.1207C>G) pathogenic?

TMPRSS3 p.Pro403Ala (c.1207C>G) is classified Likely pathogenic in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-13). AlphaMissense: likely pathogenic (0.8147); Very rare (popmax 8.47e-05%, nfe).

How common is TMPRSS3 p.Pro403Ala (c.1207C>G) in the general population?

TMPRSS3 p.Pro403Ala (c.1207C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TMPRSS3 p.Pro403Ala (c.1207C>G)?

AlphaMissense predicts likely pathogenic (score 0.8147) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Pro403Ala

c.1207C>G · VCV3607665

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8147 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8147	likely pathogenic ✓ concordant with ClinVar
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -13.47	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P404A vs ClinVar P403A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,002 alleles

Overall 6.2e-05% 1/1,613,638 alleles · very rare exomes 1/1,461,480 · genomes 0/152,158 · 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.Pro403Ala
Coding: c.1207C>G
MANE Select: NM_001256317
Type: single nucleotide variant
Location: chr21:42375853 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 404 UniProt numbering: a UniProt-annotated variant site (in dfnb8; fails to undergo proteolytic cleavage and is unable to activate enac); the peptidase s1 domain

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

Similar variants

TMPRSS3 p.Pro403Leu Pathogenic/Likely pathogenic ★★ same residue
TMPRSS3 p.Pro403fs Likely pathogenic ★ same residue
TMPRSS3 c.1049-4G>A Likely pathogenic ★★ same type
TMPRSS3 c.206-2A>G Likely pathogenic ★★ same type
TMPRSS3 c.323-6G>A Pathogenic/Likely pathogenic ★★ same type
TMPRSS3 c.446+1G>T Likely pathogenic ★★ same type
TMPRSS3 c.573-1G>A Likely pathogenic ★★ same type
TMPRSS3 p.Ala138Glu Pathogenic/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-pro403ala (accessed [today's date]).

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