Is TMPRSS3 p.Ala359Val (c.1076C>T) pathogenic?

TMPRSS3 p.Ala359Val (c.1076C>T) is classified Uncertain significance in TMPRSS3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.3052); Ultra-rare (popmax 0.0134%, eas); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS3 p.Ala359Val (c.1076C>T)?

TMPRSS3 p.Ala359Val (c.1076C>T) is associated with Inborn genetic diseases, hearing loss disorder (ClinVar).

How common is TMPRSS3 p.Ala359Val (c.1076C>T) in the general population?

TMPRSS3 p.Ala359Val (c.1076C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about TMPRSS3 p.Ala359Val (c.1076C>T)?

AlphaMissense predicts likely benign (score 0.3052) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Ala359Val

c.1076C>T · rs200777266 · VCV1049835

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.3052 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3052	likely benign
REVEL	0.385	indeterminate
SaProt	LLR -6.54	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 8.4	GERP 1.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	26.2	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A360V vs ClinVar A359V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,896 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00235% 38/1,614,018 alleles · ultra-rare exomes 27/1,461,802 · genomes 11/152,216 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,483
African / African-American	0.00934%	10,705
European (non-Finnish)	0.00203%	49,168
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Ala359Val
Coding: c.1076C>T
MANE Select: NM_001256317
dbSNP: rs200777266
Type: single nucleotide variant
Location: chr21:42376656 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 360 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

Also linked: hearing loss disorder

Similar variants

TMPRSS3 p.Ala359= Conflicting classifications of pathogenicity ★ same residue
TMPRSS3 c.323-6G>A Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Ala138Glu Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Ala306Thr Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Arg106Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
TMPRSS3 p.Trp251Cys Pathogenic ★★ same condition
TMPRSS3 p.Ala195Val Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Ala352Thr 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-ala359val (accessed [today's date]).

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