Is TMPRSS4 p.Ala44Val (c.131C>T) pathogenic?

TMPRSS4 p.Ala44Val (c.131C>T) is classified Likely benign in TMPRSS4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-11-21). AlphaMissense: likely benign (0.092); Rare (popmax 0.462%, mid).

How common is TMPRSS4 p.Ala44Val (c.131C>T) in the general population?

TMPRSS4 p.Ala44Val (c.131C>T) is rare (popmax 0.462%, mid) (gnomAD).

What do computational predictors say about TMPRSS4 p.Ala44Val (c.131C>T)?

AlphaMissense predicts likely benign (score 0.092) — an in-silico prediction, not a clinical call.

TMPRSS4 p.Ala44Val

c.131C>T · rs148550252 · VCV1315695

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.092 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.462%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.092	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.98	donor loss · deltas
Pangolin	Δ0.80	gain · loss 0.79 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP -0.39	GERP -2.8
Regional constraint	o/e 0.98	unconstrained · MANE · 41 kb · p 0.65 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.462% Middle Eastern · 28/6,058 alleles

Filtering AF 0.328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.283%

Overall 0.0485% 782/1,613,860 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.462%	216
European (non-Finnish)	0.0569%	1,758
Remaining individualsnot grpmax-eligible	0.056%	1,786
Admixed American	0.0233%	4,286
Finnishnot grpmax-eligible	0.0188%	5,333
African / African-American	0.016%	6,245
South Asian	0.011%	9,107

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: TMPRSS4
Protein: p.Ala44Val
Coding: c.131C>T
MANE Select: NM_019894
dbSNP: rs148550252
Type: single nucleotide variant
Location: chr11:118099072 (GRCh38)
Gene constraint: LOEUF 0.94 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.01

Full TMPRSS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMPRSS4 p.Ala44Thr Uncertain significance ★ ⚠ same residue
CAP2 p.Arg17His Uncertain significance ★★ ⚠ same type
CAP2 p.His203Arg Uncertain significance ★★ ⚠ same type
CAP2 c.1003-5T>G Uncertain significance ★ same type
CAP2 p.Ala162Thr Uncertain significance ★ ⚠ same type
CAP2 p.Ala262Pro Uncertain significance ★ ⚠ same type
CAP2 p.Ala272Thr Uncertain significance ★ ⚠ same type
CAP2 p.Ala294Thr Uncertain significance ★ ⚠ 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/tmprss4-p-ala44val (accessed [today's date]).

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