Is TMPRSS3 p.Ile65Val (c.193A>G) pathogenic?

TMPRSS3 p.Ile65Val (c.193A>G) is classified Uncertain significance in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.0603); Ultra-rare (popmax 0.0223%, eas); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS3 p.Ile65Val (c.193A>G)?

TMPRSS3 p.Ile65Val (c.193A>G) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS3 p.Ile65Val (c.193A>G) in the general population?

TMPRSS3 p.Ile65Val (c.193A>G) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about TMPRSS3 p.Ile65Val (c.193A>G)?

AlphaMissense predicts likely benign (score 0.0603) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Ile65Val

c.193A>G · VCV4187515

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0603 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0603	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -7.13	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 0.54	GERP 1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	16.71	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 0.0223% East Asian · 10/44,874 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00917%

Overall 0.0013% 21/1,612,788 alleles · ultra-rare exomes 13/1,460,450 · genomes 8/152,338 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,487
African / African-American	0.00933%	10,718
South Asian	0.00329%	30,354
Remaining individualsnot grpmax-eligible	0.0016%	62,452

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.Ile65Val
Coding: c.193A>G
MANE Select: NM_001256317
Type: single nucleotide variant
Location: chr21:42389939 (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-ile65val (accessed [today's date]).

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