Is TMPRSS3 p.Ala64Val (c.191C>T) pathogenic?

TMPRSS3 p.Ala64Val (c.191C>T) is classified Uncertain significance in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: likely benign (0.2276); Very rare (popmax 0.000594%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS3 p.Ala64Val (c.191C>T)?

TMPRSS3 p.Ala64Val (c.191C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS3 p.Ala64Val (c.191C>T) in the general population?

TMPRSS3 p.Ala64Val (c.191C>T) is very rare (popmax 0.000594%, nfe) (gnomAD).

What do computational predictors say about TMPRSS3 p.Ala64Val (c.191C>T)?

AlphaMissense predicts likely benign (score 0.2276) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Ala64Val

c.191C>T · VCV3458860

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2276 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2276	likely benign
REVEL	0.508	indeterminate
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	25.5	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 0.000594% European (non-Finnish) · 7/1,178,624 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,612,628 alleles · very rare exomes 7/1,460,332 · genomes 0/152,296 · joint denominator

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.Ala64Val
Coding: c.191C>T
MANE Select: NM_001256317
Type: single nucleotide variant
Location: chr21:42389941 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09

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-ala64val (accessed [today's date]).

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