Is TMPRSS3 p.Arg166Gln (c.497G>A) pathogenic?

TMPRSS3 p.Arg166Gln (c.497G>A) is classified Likely benign in TMPRSS3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-15). AlphaMissense: likely benign (0.0594); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS3 p.Arg166Gln (c.497G>A)?

TMPRSS3 p.Arg166Gln (c.497G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS3 p.Arg166Gln (c.497G>A) in the general population?

TMPRSS3 p.Arg166Gln (c.497G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about TMPRSS3 p.Arg166Gln (c.497G>A)?

AlphaMissense predicts likely benign (score 0.0594) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Arg166Gln

c.497G>A · rs150397427 · VCV666766

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0594	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -3.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -3.3
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	0.085	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00186% 30/1,614,050 alleles · very rare exomes 25/1,461,876 · genomes 5/152,174 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,439
South Asian	0.00329%	30,361
European (non-Finnish)	0.00195%	51,306
Admixed American	0.00167%	60,012
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Arg166Gln
Coding: c.497G>A
MANE Select: NM_001256317
dbSNP: rs150397427
Type: single nucleotide variant
Location: chr21:42385484 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 166: the srcr domain

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

Similar variants

TMPRSS3 p.Arg166Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TMPRSS3 p.Arg166Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
TMPRSS3 p.Ala195Val Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Ala352Thr Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Ala359Val Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Arg106His Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Asp131Asn Uncertain significance ★★ ⚠ same condition
TMPRSS3 p.Asp132Gly Uncertain significance ★★ ⚠ 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-arg166gln (accessed [today's date]).

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