Is TMPRSS3 p.Ala386Val (c.1157C>T) pathogenic?

TMPRSS3 p.Ala386Val (c.1157C>T) is classified Conflicting classifications of pathogenicity in TMPRSS3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-23). AlphaMissense: likely pathogenic (0.9335); Ultra-rare (popmax 0.0133%, afr).

How common is TMPRSS3 p.Ala386Val (c.1157C>T) in the general population?

TMPRSS3 p.Ala386Val (c.1157C>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about TMPRSS3 p.Ala386Val (c.1157C>T)?

AlphaMissense predicts likely pathogenic (score 0.9335) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Ala386Val

c.1157C>T · rs201172277 · VCV3017257

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9335 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9335	likely pathogenic
REVEL	0.841	moderately pathogenic-leaning
SaProt	LLR -13.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	28.1	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 A387V vs ClinVar A386V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% African / African-American · 10/74,940 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00359% 58/1,613,668 alleles · ultra-rare exomes 46/1,461,444 · genomes 12/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,494
Remaining individualsnot grpmax-eligible	0.0048%	20,825
Admixed American	0.00333%	30,003
European (non-Finnish)	0.00331%	30,257
Finnishnot grpmax-eligible	0.00314%	31,843
South Asian	0.0022%	45,542

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.Ala386Val
Coding: c.1157C>T
MANE Select: NM_001256317
dbSNP: rs201172277
Type: single nucleotide variant
Location: chr21:42376575 (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.Ala386Pro Likely pathogenic ★ 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-ala386val (accessed [today's date]).

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