Is TMPRSS3 p.Arg435His (c.1304G>A) pathogenic?

TMPRSS3 p.Arg435His (c.1304G>A) is classified Conflicting classifications of pathogenicity in TMPRSS3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-12). AlphaMissense: ambiguous (0.3591); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS3 p.Arg435His (c.1304G>A)?

TMPRSS3 p.Arg435His (c.1304G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS3 p.Arg435His (c.1304G>A) in the general population?

TMPRSS3 p.Arg435His (c.1304G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TMPRSS3 p.Arg435His (c.1304G>A)?

AlphaMissense predicts ambiguous (score 0.3591) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Arg435His

c.1304G>A · rs769807644 · VCV1961947

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3591 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3591	ambiguous
REVEL	0.554	indeterminate
SaProt	LLR -13.45	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP -0.85, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R436H vs ClinVar R435H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,026 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000929% 15/1,613,804 alleles · very rare exomes 15/1,461,520 · genomes 0/152,284 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,026
Remaining individualsnot grpmax-eligible	0.0016%	62,498
European (non-Finnish)	0.0011%	90,771

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.Arg435His
Coding: c.1304G>A
MANE Select: NM_001256317
dbSNP: rs769807644
Type: single nucleotide variant
Location: chr21:42375756 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 436 UniProt numbering: 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.Arg435Gly Uncertain significance ★★ ⚠ same residue
TMPRSS3 p.Arg435Leu Likely pathogenic ★ same residue
TMPRSS3 p.Arg435Pro Pathogenic ★ same residue
TMPRSS3 p.Arg435Cys Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg435his (accessed [today's date]).

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