Is TMPRSS3 p.Arg80Cys (c.238C>T) pathogenic?

TMPRSS3 p.Arg80Cys (c.238C>T) is classified Conflicting classifications of pathogenicity in TMPRSS3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-06-24). AlphaMissense: likely benign (0.2965); Ultra-rare (popmax 0.0164%, mid).

How common is TMPRSS3 p.Arg80Cys (c.238C>T) in the general population?

TMPRSS3 p.Arg80Cys (c.238C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about TMPRSS3 p.Arg80Cys (c.238C>T)?

AlphaMissense predicts likely benign (score 0.2965) — an in-silico prediction, not a clinical call.

TMPRSS3 p.Arg80Cys

c.238C>T · rs143733205 · VCV228296

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2965 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2965	likely benign
REVEL	0.602	indeterminate
SaProt	LLR -10.45	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 23 kb · p 0.49 · regional, not allelic
Overall
CADD	23.9	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00595% 96/1,614,074 alleles · ultra-rare exomes 86/1,461,836 · genomes 10/152,238 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.0133%	7,493
East Asian	0.00668%	14,964
European (non-Finnish)	0.00661%	15,129
Remaining individualsnot grpmax-eligible	0.0032%	31,243
South Asian	0.0022%	45,543

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.Arg80Cys
Coding: c.238C>T
MANE Select: NM_001256317
dbSNP: rs143733205
Type: single nucleotide variant
Location: chr21:42389013 (GRCh38)
Gene constraint: LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.09
Residue 80: the ldl-receptor class a domain

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

Similar variants

TMPRSS3 p.Arg80His Conflicting classifications of pathogenicity ★ ⚠ same residue
TMPRSS3 c.1049-4G>A Likely pathogenic ★★ same type
TMPRSS3 c.206-2A>G Likely pathogenic ★★ same type
TMPRSS3 c.323-6G>A Pathogenic/Likely pathogenic ★★ same type
TMPRSS3 c.446+1G>T Likely pathogenic ★★ same type
TMPRSS3 c.573-1G>A Likely pathogenic ★★ same type
TMPRSS3 p.Ala138Glu Pathogenic/Likely pathogenic ★★ same type
TMPRSS3 p.Ala306Thr Pathogenic/Likely pathogenic ★★ same type

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-arg80cys (accessed [today's date]).

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