Is TMPRSS3 p.Cys424= (c.1272C>T) pathogenic?

TMPRSS3 p.Cys424= (c.1272C>T) is classified Conflicting classifications of pathogenicity in TMPRSS3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-08-01). Rare (popmax 0.115%, mid); Associated with autosomal recessive nonsyndromic hearing loss 8.

What condition is associated with TMPRSS3 p.Cys424= (c.1272C>T)?

TMPRSS3 p.Cys424= (c.1272C>T) is associated with autosomal recessive nonsyndromic hearing loss 8 (ClinVar).

How common is TMPRSS3 p.Cys424= (c.1272C>T) in the general population?

TMPRSS3 p.Cys424= (c.1272C>T) is rare (popmax 0.115%, mid) (gnomAD).

TMPRSS3 p.Cys424=

c.1272C>T · rs56178910 · VCV46101

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Conditions

autosomal recessive nonsyndromic hearing loss 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.76	GERP -5
Overall
CADD	4.487	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.115% Middle Eastern · 7/6,062 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0502%

Overall 0.0439% 709/1,613,612 alleles · rare exomes 649/1,461,440 · genomes 60/152,172 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	866
European (non-Finnish)	0.0552%	1,813
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,973
Remaining individualsnot grpmax-eligible	0.0224%	4,464
Admixed American	0.0117%	8,574
South Asian	0.00878%	11,384
African / African-American	0.00533%	18,755
Finnishnot grpmax-eligible	0.00472%	21,198

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.Cys424=
Coding: c.1272C>T
MANE Select: NM_001256317
dbSNP: rs56178910
Type: single nucleotide variant
Location: chr21:42375788 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 424: the peptidase s1 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.Cys424Ter Likely pathogenic ★ 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-cys424 (accessed [today's date]).

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