Is TMPRSS3 p.Ala386Pro (c.1156G>C) pathogenic?

TMPRSS3 p.Ala386Pro (c.1156G>C) is classified Likely pathogenic in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-28). AlphaMissense: likely pathogenic (0.9944); Absent from gnomAD v4.1.

How common is TMPRSS3 p.Ala386Pro (c.1156G>C) in the general population?

TMPRSS3 p.Ala386Pro (c.1156G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMPRSS3 p.Ala386Pro (c.1156G>C)?

AlphaMissense predicts likely pathogenic (score 0.9944) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Ala386Pro

c.1156G>C · rs781376204 · VCV2772340

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9944 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9944	likely pathogenic ✓ concordant with ClinVar · top 3% in TMPRSS3
REVEL	0.9	moderately pathogenic-leaning
SaProt	LLR -14.39	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 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	25.6	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 A387P vs ClinVar A386P) — verify the residue.

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.Ala386Pro
Coding: c.1156G>C
MANE Select: NM_001256317
dbSNP: rs781376204
Type: single nucleotide variant
Location: chr21:42376576 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 387 UniProt numbering: the peptidase s1 domain

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

Similar variants

TMPRSS3 p.Ala386Thr Pathogenic ★★ same residue
TMPRSS3 p.Ala386Val Conflicting classifications of pathogenicity ★ ⚠ same residue
TMPRSS3 p.Ala386= Likely benign ★ 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

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-ala386pro (accessed [today's date]).

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