Is TMPRSS3 p.Ala123Val (c.368C>T) pathogenic?

TMPRSS3 p.Ala123Val (c.368C>T) is classified Uncertain significance in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-27). AlphaMissense: likely benign (0.1677); Ultra-rare (popmax 0.0167%, amr).

How common is TMPRSS3 p.Ala123Val (c.368C>T) in the general population?

TMPRSS3 p.Ala123Val (c.368C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about TMPRSS3 p.Ala123Val (c.368C>T)?

AlphaMissense predicts likely benign (score 0.1677) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Ala123Val

c.368C>T · rs769346020 · VCV2663560

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1677 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1677	likely benign
REVEL	0.298	indeterminate
SaProt	LLR -7.47	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8	GERP 2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/60,020 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000743% 12/1,614,214 alleles · ultra-rare exomes 12/1,461,888 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,002
South Asian	0.0022%	45,540

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.Ala123Val
Coding: c.368C>T
MANE Select: NM_001256317
dbSNP: rs769346020
Type: single nucleotide variant
Location: chr21:42388481 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 123: the srcr domain

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

Similar variants

TMPRSS3 p.Ala123Ser Uncertain significance ★ ⚠ 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
TMPRSS3 p.Ala306Thr 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-ala123val (accessed [today's date]).

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