Is TMPRSS3 p.His70fs (c.208del) pathogenic?

TMPRSS3 p.His70fs (c.208del) is classified Pathogenic/Likely pathogenic in TMPRSS3 (ClinVar, Multiple submitters, 26 submitters; last evaluated 2026-06-24). Rare (popmax 0.102%, nfe); Associated with TMPRSS3-related disorder.

What condition is associated with TMPRSS3 p.His70fs (c.208del)?

TMPRSS3 p.His70fs (c.208del) is associated with TMPRSS3-related disorder, hearing loss disorder, autosomal recessive nonsyndromic hearing loss 8 (ClinVar).

How common is TMPRSS3 p.His70fs (c.208del) in the general population?

TMPRSS3 p.His70fs (c.208del) is rare (popmax 0.102%, nfe) (gnomAD).

TMPRSS3 p.His70fs

c.208del · rs727503493 · VCV165492

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 26 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.102%, nfe)

Conditions

TMPRSS3-related disorder

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 4 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Overall
CADD	31.0	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 0.102% European (non-Finnish) · 1,202/1,180,022 alleles

Filtering AF 0.0971% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0951%

Overall 0.0815% 1,315/1,614,124 alleles · rare exomes 1,234/1,461,792 · genomes 81/152,332 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.102%	982
Remaining individualsnot grpmax-eligible	0.101%	992
Ashkenazi Jewishnot grpmax-eligible	0.0743%	1,346
African / African-American	0.024%	4,169
Admixed American	0.0117%	8,575
South Asian	0.0022%	45,541
Finnishnot grpmax-eligible	0.00156%	63,972

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.His70fs
Coding: c.208del
MANE Select: NM_001256317
dbSNP: rs727503493
Type: Deletion
Location: chr21:42389043 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09

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

Disease context

TMPRSS3-related disorder

Also linked: hearing loss disorder autosomal recessive nonsyndromic hearing loss 8 nonsyndromic genetic hearing loss

Similar variants

TMPRSS3 p.Asp334fs Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Gln144fs Pathogenic ★★ same condition
TMPRSS3 p.Ser215fs Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Val337fs Pathogenic/Likely pathogenic ★★ same condition
TMPRSS3 p.Leu250fs Pathogenic ★ same condition
TMPRSS3 p.Glu408fs Conflicting classifications of pathogenicity ★ same condition
TMPRSS3 p.Asp100fs Likely pathogenic same condition
TMPRSS3 c.1049-4G>A 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-his70fs (accessed [today's date]).

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