Is TMPRSS3 p.Val116Ala (c.347T>C) pathogenic?

TMPRSS3 p.Val116Ala (c.347T>C) is classified Conflicting classifications of pathogenicity in TMPRSS3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-08). AlphaMissense: likely benign (0.1086); Rare (popmax 0.18%, amr); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS3 p.Val116Ala (c.347T>C)?

TMPRSS3 p.Val116Ala (c.347T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS3 p.Val116Ala (c.347T>C) in the general population?

TMPRSS3 p.Val116Ala (c.347T>C) is rare (popmax 0.18%, amr) (gnomAD).

What do computational predictors say about TMPRSS3 p.Val116Ala (c.347T>C)?

AlphaMissense predicts likely benign (score 0.1086) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Val116Ala

c.347T>C · rs201007237 · VCV46117

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1086 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.18%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1086	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -8.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.2	GERP -4.1, phastCons 0.055
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	11.52	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 0.18% Admixed American · 108/60,016 alleles

Filtering AF 0.152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.142%

Overall 0.00675% 109/1,614,090 alleles · rare exomes 35/1,461,892 · genomes 74/152,198 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.18%	556
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Val116Ala
Coding: c.347T>C
MANE Select: NM_001256317
dbSNP: rs201007237
Type: single nucleotide variant
Location: chr21:42388502 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 116: the srcr 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.Val116Met Pathogenic/Likely pathogenic ★★ ⚠ same residue
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

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-val116ala (accessed [today's date]).

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