Is TMPRSS3 p.Ala359= (c.1077G>A) pathogenic?

TMPRSS3 p.Ala359= (c.1077G>A) is classified Conflicting classifications of pathogenicity in TMPRSS3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-31). Very rare (popmax 0.00439%, sas); Associated with autosomal recessive nonsyndromic hearing loss 8.

What condition is associated with TMPRSS3 p.Ala359= (c.1077G>A)?

TMPRSS3 p.Ala359= (c.1077G>A) is associated with autosomal recessive nonsyndromic hearing loss 8 (ClinVar).

How common is TMPRSS3 p.Ala359= (c.1077G>A) in the general population?

TMPRSS3 p.Ala359= (c.1077G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

TMPRSS3 p.Ala359=

c.1077G>A · rs756432794 · VCV898535

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -4.3
Overall
CADD	1.879	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,080 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00211% 34/1,613,920 alleles · very rare exomes 33/1,461,788 · genomes 1/152,132 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,230
Remaining individualsnot grpmax-eligible	0.008%	12,496
South Asiangrpmax	0.00439%	22,770
East Asian	0.00223%	44,896
European (non-Finnish)	0.00136%	73,752
African / African-American	0.00134%	74,902

Ashkenazi Jewish 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.Ala359=
Coding: c.1077G>A
MANE Select: NM_001256317
dbSNP: rs756432794
Type: single nucleotide variant
Location: chr21:42376655 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 359: 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.Ala359Val Uncertain significance ★★ ⚠ 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-ala359 (accessed [today's date]).

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