Is TMPRSS3 p.Pro229Ser (c.685C>T) pathogenic?

TMPRSS3 p.Pro229Ser (c.685C>T) is classified Uncertain significance in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely pathogenic (0.8785); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS3 p.Pro229Ser (c.685C>T)?

TMPRSS3 p.Pro229Ser (c.685C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS3 p.Pro229Ser (c.685C>T) in the general population?

TMPRSS3 p.Pro229Ser (c.685C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about TMPRSS3 p.Pro229Ser (c.685C>T)?

AlphaMissense predicts likely pathogenic (score 0.8785) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Pro229Ser

c.685C>T · VCV3971070

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8785 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8785	likely pathogenic
REVEL	0.95	strongly pathogenic-leaning
SaProt	LLR -11.35	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 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	28.2	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,940 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,614,072 alleles · very rare exomes 3/1,461,834 · genomes 1/152,238 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,980
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Pro229Ser
Coding: c.685C>T
MANE Select: NM_001256317
Type: single nucleotide variant
Location: chr21:42383130 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 229: 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.Pro229= Likely benign ★ same residue
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

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-pro229ser (accessed [today's date]).

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