Is ART1 p.Tyr75Cys (c.224A>G) pathogenic?

ART1 p.Tyr75Cys (c.224A>G) is classified Uncertain significance in ART1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-17). AlphaMissense: likely pathogenic (0.8094); Ultra-rare (popmax 0.0436%, nfe).

How common is ART1 p.Tyr75Cys (c.224A>G) in the general population?

ART1 p.Tyr75Cys (c.224A>G) is ultra-rare (popmax 0.0436%, nfe) (gnomAD).

What do computational predictors say about ART1 p.Tyr75Cys (c.224A>G)?

AlphaMissense predicts likely pathogenic (score 0.8094) — an in-silico prediction, not a clinical call.

ART1 p.Tyr75Cys

c.224A>G · rs369199723 · VCV2365990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8094 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0436%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8094	likely pathogenic
REVEL	0.212	benign-leaning
SaProt	LLR -11.48	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Pangolin	Δ0.55	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.2	GERP 0.42, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 4,972 bp · p 0.0056 · regional, not allelic
Overall
CADD	23.7	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 0.0436% European (non-Finnish) · 514/1,179,998 alleles

Filtering AF 0.0404% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0392%

Overall 0.0328% 529/1,613,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0436%	2,296
Remaining individualsnot grpmax-eligible	0.0144%	6,942
African / African-American	0.00801%	12,488

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: ART1
Protein: p.Tyr75Cys
Coding: c.224A>G
MANE Select: NM_004314
dbSNP: rs369199723
Type: single nucleotide variant
Location: chr11:3659743 (GRCh38)
Gene constraint: LOEUF 1.476 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.03
Residue 75: a disulfide bond; the tr mart core domain

Full ART1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ART1 p.Arg140= Benign ★★ same type
ART1 p.Leu43= Benign ★★ same type
ART1 p.Ala120Pro Uncertain significance ★ ⚠ same type
ART1 p.Ala133Val Uncertain significance ★ ⚠ same type
ART1 p.Ala138Val Uncertain significance ★ ⚠ same type
ART1 p.Ala161Ser Uncertain significance ★ ⚠ same type
ART1 p.Ala227Gly Uncertain significance ★ ⚠ same type
ART1 p.Ala227Ser Uncertain significance ★ ⚠ 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/art1-p-tyr75cys (accessed [today's date]).

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