Is TMPRSS3 p.Asp334fs (c.999del) pathogenic?

TMPRSS3 p.Asp334fs (c.999del) is classified Pathogenic/Likely pathogenic in TMPRSS3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-12). Very rare (popmax 0.000678%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 8.

What condition is associated with TMPRSS3 p.Asp334fs (c.999del)?

TMPRSS3 p.Asp334fs (c.999del) is associated with autosomal recessive nonsyndromic hearing loss 8 (ClinVar).

How common is TMPRSS3 p.Asp334fs (c.999del) in the general population?

TMPRSS3 p.Asp334fs (c.999del) is very rare (popmax 0.000678%, nfe) (gnomAD).

TMPRSS3 p.Asp334fs

c.999del · rs748150602 · VCV2138389

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

autosomal recessive nonsyndromic hearing loss 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.7	GERP -1.2, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,180,014 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,614,150 alleles · very rare exomes 9/1,461,876 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)grpmax	0.000678%	147,502

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp334fs
Coding: c.999del
MANE Select: NM_001256317
dbSNP: rs748150602
Type: Deletion
Location: chr21:42380166 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 334: 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.Gln144fs Pathogenic ★★ same condition
TMPRSS3 p.His70fs Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Ser215fs Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Leu250fs Pathogenic ★ same condition
TMPRSS3 p.Asp334Asn Uncertain significance ★ ⚠ same residue
TMPRSS3 p.Asp334His Uncertain significance ★ ⚠ same residue
TMPRSS3 p.Glu408fs Conflicting classifications of pathogenicity ★ same condition
TMPRSS3 p.Asp334= Likely benign ★ same residue

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-asp334fs (accessed [today's date]).

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