Is TMPRSS3 p.Pro6Leu (c.17C>T) pathogenic?

TMPRSS3 p.Pro6Leu (c.17C>T) is classified Uncertain significance in TMPRSS3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-05). AlphaMissense: likely benign (0.0677); Very rare (popmax 0.00814%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS3 p.Pro6Leu (c.17C>T)?

TMPRSS3 p.Pro6Leu (c.17C>T) is associated with Inborn genetic diseases, autosomal recessive nonsyndromic hearing loss 8 (ClinVar).

How common is TMPRSS3 p.Pro6Leu (c.17C>T) in the general population?

TMPRSS3 p.Pro6Leu (c.17C>T) is very rare (popmax 0.00814%, nfe) (gnomAD).

What do computational predictors say about TMPRSS3 p.Pro6Leu (c.17C>T)?

AlphaMissense predicts likely benign (score 0.0677) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Pro6Leu

c.17C>T · rs139865555 · VCV340061

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0677 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00814%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0677	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.3	GERP 0.033, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	19.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00814% European (non-Finnish) · 96/1,179,996 alleles

Filtering AF 0.00681% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.0062% 100/1,613,958 alleles · very rare exomes 98/1,461,822 · genomes 2/152,136 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00814%	12,292
East Asian	0.00668%	14,965
South Asian	0.0011%	91,080

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.Pro6Leu
Coding: c.17C>T
MANE Select: NM_001256317
dbSNP: rs139865555
Type: single nucleotide variant
Location: chr21:42395401 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 8

Similar variants

TMPRSS3 p.Pro6= Likely benign ★ 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-pro6leu (accessed [today's date]).

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