Is ART4 p.Val236Ile (c.706G>A) pathogenic?

ART4 p.Val236Ile (c.706G>A) is classified Uncertain significance in ART4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0801); Very rare (popmax 0.00333%, amr).

How common is ART4 p.Val236Ile (c.706G>A) in the general population?

ART4 p.Val236Ile (c.706G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ART4 p.Val236Ile (c.706G>A)?

AlphaMissense predicts likely benign (score 0.0801) — an in-silico prediction, not a clinical call.

ART4 p.Val236Ile

c.706G>A · rs768235727 · VCV2221489

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0801 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0801	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -3.53	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 -0.27	GERP 0.077, phastCons 0.002
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.58 · regional, not allelic
Overall
CADD	5.769	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 0.00333% Admixed American · 2/59,994 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000434% 7/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,997
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00267%	37,468
European (non-Finnish)	8.47e-05%	1,180,034

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: ART4
Protein: p.Val236Ile
Coding: c.706G>A
MANE Select: NM_021071
dbSNP: rs768235727
Type: single nucleotide variant
Location: chr12:14840592 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.00
Residue 236: a disulfide bond; the tr mart core domain

Full ART4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ART4 p.Ala103Val Uncertain significance ★ ⚠ same type
ART4 p.Ala20Ser Uncertain significance ★ ⚠ same type
ART4 p.Ala50Thr Uncertain significance ★ ⚠ same type
ART4 p.Ala58Thr Uncertain significance ★ ⚠ same type
ART4 p.Arg171Lys Uncertain significance ★ ⚠ same type
ART4 p.Arg171Thr Uncertain significance ★ ⚠ same type
ART4 p.Arg263Gly Uncertain significance ★ ⚠ same type
ART4 p.Asn257Ser 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/art4-p-val236ile (accessed [today's date]).

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