Is TMPRSS3 p.Val374Met (c.1120G>A) pathogenic?

TMPRSS3 p.Val374Met (c.1120G>A) is classified Uncertain significance in TMPRSS3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-03-28). AlphaMissense: ambiguous (0.3558); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS3 p.Val374Met (c.1120G>A)?

TMPRSS3 p.Val374Met (c.1120G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS3 p.Val374Met (c.1120G>A) in the general population?

TMPRSS3 p.Val374Met (c.1120G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about TMPRSS3 p.Val374Met (c.1120G>A)?

AlphaMissense predicts ambiguous (score 0.3558) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Val374Met

c.1120G>A · rs775508015 · VCV517358

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3558 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3558	ambiguous
REVEL	0.397	indeterminate
SaProt	LLR -9.06	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.3, 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 V375M vs ClinVar V374M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,914 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00217% 35/1,613,946 alleles · very rare exomes 32/1,461,756 · genomes 3/152,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,728
Finnishnot grpmax-eligible	0.00313%	31,965
European (non-Finnish)	0.00229%	43,705
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Val374Met
Coding: c.1120G>A
MANE Select: NM_001256317
dbSNP: rs775508015
Type: single nucleotide variant
Location: chr21:42376612 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 375 UniProt numbering: the peptidase s1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMPRSS3 p.Ala195Val Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Ala352Thr Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Ala359Val Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Arg106His Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Asp131Asn Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Asp132Gly Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Cys396Phe Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Gly335Ala 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-val374met (accessed [today's date]).

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