Is ART1 p.Pro228Ser (c.682C>T) pathogenic?

ART1 p.Pro228Ser (c.682C>T) is classified Uncertain significance in ART1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.1012); Ultra-rare (popmax 0.0296%, sas).

How common is ART1 p.Pro228Ser (c.682C>T) in the general population?

ART1 p.Pro228Ser (c.682C>T) is ultra-rare (popmax 0.0296%, sas) (gnomAD).

What do computational predictors say about ART1 p.Pro228Ser (c.682C>T)?

AlphaMissense predicts likely benign (score 0.1012) — an in-silico prediction, not a clinical call.

ART1 p.Pro228Ser

c.682C>T · VCV3432945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1012 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0296%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1012	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -7.79	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 3.5	GERP 1.9, phastCons 0.96
Regional constraint	o/e 1.13	unconstrained · MANE · 4,972 bp · p 0.0056 · regional, not allelic
Overall
CADD	19.59	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 0.0296% South Asian · 27/91,082 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00192% 31/1,613,936 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0296%	3,373
Remaining individualsnot grpmax-eligible	0.0064%	15,622

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.Pro228Ser
Coding: c.682C>T
MANE Select: NM_004314
Type: single nucleotide variant
Location: chr11:3660201 (GRCh38)
Gene constraint: LOEUF 1.476 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.03
Residue 228: 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-pro228ser (accessed [today's date]).

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