Is TMPRSS3 p.Arg80His (c.239G>A) pathogenic?

TMPRSS3 p.Arg80His (c.239G>A) is classified Conflicting classifications of pathogenicity in TMPRSS3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-07-15). AlphaMissense: likely benign (0.0782); Rare (popmax 0.341%, eas); Associated with autosomal recessive nonsyndromic hearing loss 8.

What condition is associated with TMPRSS3 p.Arg80His (c.239G>A)?

TMPRSS3 p.Arg80His (c.239G>A) is associated with autosomal recessive nonsyndromic hearing loss 8 (ClinVar).

How common is TMPRSS3 p.Arg80His (c.239G>A) in the general population?

TMPRSS3 p.Arg80His (c.239G>A) is rare (popmax 0.341%, eas) (gnomAD).

What do computational predictors say about TMPRSS3 p.Arg80His (c.239G>A)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Arg80His

c.239G>A · rs146159479 · VCV179855

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.341%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal recessive nonsyndromic hearing loss 8

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.355	indeterminate
SaProt	LLR -6.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	18.77	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.341% East Asian · 153/44,882 alleles

Filtering AF 0.297% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.28%

Overall 0.0186% 301/1,614,124 alleles · rare exomes 274/1,461,848 · genomes 27/152,276 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.341%	293
Ashkenazi Jewishnot grpmax-eligible	0.297%	336
Remaining individualsnot grpmax-eligible	0.0368%	2,718
South Asian	0.00439%	22,769
Admixed American	0.00333%	30,012
European (non-Finnish)	0.00254%	39,334
African / African-American	0.00133%	75,024

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.Arg80His
Coding: c.239G>A
MANE Select: NM_001256317
dbSNP: rs146159479
Type: single nucleotide variant
Location: chr21:42389012 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 80: the ldl-receptor class a domain

Full TMPRSS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive nonsyndromic hearing loss 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMPRSS3 p.Arg80Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
TMPRSS3 c.1049-4G>A Likely pathogenic ★★ same condition
TMPRSS3 c.206-2A>G Likely pathogenic ★★ same condition
TMPRSS3 c.323-6G>A Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 c.446+1G>T Likely pathogenic ★★ same condition
TMPRSS3 c.573-1G>A Likely pathogenic ★★ same condition
TMPRSS3 p.Ala138Glu Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Ala306Thr Pathogenic/Likely pathogenic ★★ 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-arg80his (accessed [today's date]).

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