Is TMPRSS3 p.Ser81Ter (c.242C>G) pathogenic?

TMPRSS3 p.Ser81Ter (c.242C>G) is classified Pathogenic in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-15). Very rare (popmax 0.00333%, amr); Associated with nonsyndromic genetic hearing loss.

What condition is associated with TMPRSS3 p.Ser81Ter (c.242C>G)?

TMPRSS3 p.Ser81Ter (c.242C>G) is associated with nonsyndromic genetic hearing loss (ClinVar).

How common is TMPRSS3 p.Ser81Ter (c.242C>G) in the general population?

TMPRSS3 p.Ser81Ter (c.242C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

How is Rare non-syndromic genetic deafness inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TMPRSS3 p.Ser81Ter

c.242C>G · rs757110501 · VCV1185592

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

nonsyndromic genetic hearing loss

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,028 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000186% 3/1,614,190 alleles · very rare exomes 3/1,461,856 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,014
European (non-Finnish)	8.47e-05%	1,180,040

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.Ser81Ter
Coding: c.242C>G
MANE Select: NM_001256317
dbSNP: rs757110501
Type: single nucleotide variant
Location: chr21:42389009 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 81: the ldl-receptor class a domain

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

Disease context

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

For Rare non-syndromic genetic deafness (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

TMPRSS3 p.Ala138Glu Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Ala425Thr Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.His70fs Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 c.1049-4G>A Likely pathogenic ★★ same type
TMPRSS3 c.206-2A>G Likely pathogenic ★★ same type
TMPRSS3 c.323-6G>A Pathogenic/Likely pathogenic ★★ same type
TMPRSS3 c.446+1G>T Likely pathogenic ★★ same type
TMPRSS3 c.573-1G>A Likely pathogenic ★★ same type

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-ser81ter (accessed [today's date]).

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