Is TMPRSS3 p.Pro403fs (c.1206dup) pathogenic?

TMPRSS3 p.Pro403fs (c.1206dup) is classified Likely pathogenic in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). Very rare (popmax 8.47e-05%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 8.

What condition is associated with TMPRSS3 p.Pro403fs (c.1206dup)?

TMPRSS3 p.Pro403fs (c.1206dup) is associated with autosomal recessive nonsyndromic hearing loss 8 (ClinVar).

How common is TMPRSS3 p.Pro403fs (c.1206dup) in the general population?

TMPRSS3 p.Pro403fs (c.1206dup) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

TMPRSS3 p.Pro403fs

c.1206dup · VCV3601932

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, 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 12 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,004 alleles

Overall 0.000124% 2/1,613,632 alleles · very rare exomes 2/1,461,474 · genomes 0/152,158 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,602
European (non-Finnish)grpmax	8.47e-05%	1,180,004

Finnish 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.Pro403fs
Coding: c.1206dup
MANE Select: NM_001256317
Type: Duplication
Location: chr21:42375853 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 403: 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.Pro403Leu Pathogenic/Likely pathogenic ★★ same residue
TMPRSS3 p.Cys194fs Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 c.617-3_617-2dup Benign ★★ same condition
TMPRSS3 p.Pro403Ala Likely pathogenic ★ same residue
TMPRSS3 p.Pro50fs Pathogenic ★ same condition
TMPRSS3 p.Ser14fs Pathogenic ★ same condition
TMPRSS3 c.1049-4G>A Likely pathogenic ★★ same condition
TMPRSS3 c.206-2A>G 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-pro403fs (accessed [today's date]).

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