Is TMPRSS3 p.Arg191Lys (c.572G>A) pathogenic?

TMPRSS3 p.Arg191Lys (c.572G>A) is classified Pathogenic in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). AlphaMissense: likely benign (0.1197); Very rare (popmax 0.00167%, amr); Associated with autosomal recessive nonsyndromic hearing loss 8.

What condition is associated with TMPRSS3 p.Arg191Lys (c.572G>A)?

TMPRSS3 p.Arg191Lys (c.572G>A) is associated with autosomal recessive nonsyndromic hearing loss 8 (ClinVar).

How common is TMPRSS3 p.Arg191Lys (c.572G>A) in the general population?

TMPRSS3 p.Arg191Lys (c.572G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TMPRSS3 p.Arg191Lys (c.572G>A)?

AlphaMissense predicts likely benign (score 0.1197) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Arg191Lys

c.572G>A · VCV3601940

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1197 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 8

Computational evidence

Protein change
AlphaMissense	0.1197	likely benign ⚠ discordant with ClinVar
REVEL	0.181	moderately benign-leaning
SaProt	LLR -5.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.73	donor loss · deltas
Pangolin	Δ0.59	loss · gain 0.31 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	22.4	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 0.00167% Admixed American · 1/59,998 alleles

Overall 0.000124% 2/1,613,866 alleles · very rare exomes 1/1,461,810 · genomes 1/152,056 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,998
European (non-Finnish)	8.47e-05%	1,179,972

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.Arg191Lys
Coding: c.572G>A
MANE Select: NM_001256317
Type: single nucleotide variant
Location: chr21:42385409 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 191: the srcr 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 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
TMPRSS3 p.Ala306Val 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-arg191lys (accessed [today's date]).

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