Is TMPRSS4 p.Pro203Arg (c.608C>G) pathogenic?

TMPRSS4 p.Pro203Arg (c.608C>G) is classified Uncertain significance in TMPRSS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: likely benign (0.104); Very rare (popmax 0.00271%, afr).

How common is TMPRSS4 p.Pro203Arg (c.608C>G) in the general population?

TMPRSS4 p.Pro203Arg (c.608C>G) is very rare (popmax 0.00271%, afr) (gnomAD).

What do computational predictors say about TMPRSS4 p.Pro203Arg (c.608C>G)?

AlphaMissense predicts likely benign (score 0.104) — an in-silico prediction, not a clinical call.

TMPRSS4 p.Pro203Arg

c.608C>G · VCV3808639

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.104 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.104	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.71, phastCons 0.39
Regional constraint	o/e 0.98	unconstrained · MANE · 41 kb · p 0.65 · regional, not allelic
Overall
CADD	19.27	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 0.00271% African / African-American · 2/73,792 alleles

Filtering AF 0.00045% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000168%

Overall 0.000313% 5/1,596,060 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00271%	36,896
European (non-Finnish)	0.000256%	390,840

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: TMPRSS4
Protein: p.Pro203Arg
Coding: c.608C>G
MANE Select: NM_019894
Type: single nucleotide variant
Location: chr11:118111765 (GRCh38)
Gene constraint: LOEUF 0.94 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.01
Residue 203: a disulfide bond; the srcr domain

Full TMPRSS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAP2 p.His203Arg Uncertain significance ★★ ⚠ same residue
CAP2 p.Arg17His Uncertain significance ★★ ⚠ same type
TMPRSS4 p.Ala44Val Likely benign ★★ same type
CAP2 c.1003-5T>G Uncertain significance ★ same type
CAP2 p.Ala162Thr Uncertain significance ★ ⚠ same type
CAP2 p.Ala262Pro Uncertain significance ★ ⚠ same type
CAP2 p.Ala272Thr Uncertain significance ★ ⚠ same type
CAP2 p.Ala294Thr Uncertain significance ★ ⚠ same type

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/tmprss4-p-pro203arg (accessed [today's date]).

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