Is TMPRSS3 p.Cys396Phe (c.1187G>T) pathogenic?

TMPRSS3 p.Cys396Phe (c.1187G>T) is classified Uncertain significance in TMPRSS3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-19). AlphaMissense: likely pathogenic (0.9973); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS3 p.Cys396Phe (c.1187G>T)?

TMPRSS3 p.Cys396Phe (c.1187G>T) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS3 p.Cys396Phe (c.1187G>T) in the general population?

TMPRSS3 p.Cys396Phe (c.1187G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about TMPRSS3 p.Cys396Phe (c.1187G>T)?

AlphaMissense predicts likely pathogenic (score 0.9973) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Cys396Phe

c.1187G>T · rs773711263 · VCV618433

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9973 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9973	likely pathogenic · top 2% in TMPRSS3
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -14.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 C397F vs ClinVar C396F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,892 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,158 alleles · very rare exomes 0/1,460,902 · genomes 2/152,256 · 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.Cys396Phe
Coding: c.1187G>T
MANE Select: NM_001256317
dbSNP: rs773711263
Type: single nucleotide variant
Location: chr21:42376545 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 397 UniProt numbering: a disulfide bond; 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

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.Gly335Ala Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Leu301Val 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-cys396phe (accessed [today's date]).

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