Is ART3 p.Phe138Leu (c.414C>G) pathogenic?

ART3 p.Phe138Leu (c.414C>G) is classified Uncertain significance in ART3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-26). AlphaMissense: likely pathogenic (0.7437); Ultra-rare (popmax 0.0173%, afr).

How common is ART3 p.Phe138Leu (c.414C>G) in the general population?

ART3 p.Phe138Leu (c.414C>G) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

What do computational predictors say about ART3 p.Phe138Leu (c.414C>G)?

AlphaMissense predicts likely pathogenic (score 0.7437) — an in-silico prediction, not a clinical call.

ART3 p.Phe138Leu

c.414C>G · rs375657911 · VCV2303179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7437 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7437	likely pathogenic · top 10% in ART3
REVEL	0.168	moderately benign-leaning
SaProt	LLR -4.67	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.041	GERP -2.3, phastCons 0.88
Regional constraint	o/e 1.00	unconstrained · MANE · 6,390 bp · p 0.96 · regional, not allelic
Overall
CADD	12.23	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 0.0173% African / African-American · 13/74,936 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.000929% 15/1,614,110 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,764
Admixed American	0.00167%	60,014
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: ART3
Protein: p.Phe138Leu
Coding: c.414C>G
MANE Select: NM_001130016
dbSNP: rs375657911
Type: single nucleotide variant
Location: chr4:76082168 (GRCh38)
Gene constraint: LOEUF 1.377 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.56
Residue 138: a disulfide bond; the tr mart core domain

Full ART3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CXCL10 p.Ala81= Benign ★★ same type
ART3 p.Ala118Val Uncertain significance ★ ⚠ same type
ART3 p.Ala14Ser Uncertain significance ★ ⚠ same type
ART3 p.Ala155Thr Uncertain significance ★ ⚠ same type
ART3 p.Ala193Gly Uncertain significance ★ ⚠ same type
ART3 p.Ala193Thr Uncertain significance ★ ⚠ same type
ART3 p.Ala382Asp Uncertain significance ★ ⚠ same type
ART3 p.Ala388Asp 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/art3-p-phe138leu (accessed [today's date]).

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