Is ART4 p.Tyr126= (c.378T>C) pathogenic?

ART4 p.Tyr126= (c.378T>C) is classified Benign in ART4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-17). Common (popmax 37.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with ART4-related disorder.

What condition is associated with ART4 p.Tyr126= (c.378T>C)?

ART4 p.Tyr126= (c.378T>C) is associated with ART4-related disorder (ClinVar).

ART4 p.Tyr126=

Q: How common is ART4 p.Tyr126= (c.378T>C) in the general population?

ART4 p.Tyr126= (c.378T>C) is common (popmax 37.9%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.378T>C · rs1861698 · VCV3060314

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 37.9%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

ART4-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	GERP -3.1, phastCons 0.55
Overall
CADD	0.996	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 37.9% Middle Eastern · 2,295/6,062 alleles

Filtering AF 37.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 37.7%

Overall 35.2% 567,425/1,614,000 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	51%	2
Middle Easterngrpmax	37.9%	3
European (non-Finnish)	37.8%	3
Admixed American	34.2%	3
Ashkenazi Jewishnot grpmax-eligible	33.9%	3
Remaining individualsnot grpmax-eligible	33.4%	3
South Asian	27.9%	4
African / African-American	27.3%	4
Finnishnot grpmax-eligible	26.8%	4
East Asian	8.93%	11

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Tyr126=
Coding: c.378T>C
MANE Select: NM_021071
dbSNP: rs1861698
Type: single nucleotide variant
Location: chr12:14840920 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.00
Residue 126: a disulfide bond; the tr mart core domain; a binding site

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

Disease context

ART4-related disorder

Similar variants

ART4 p.Tyr126Cys Uncertain significance ★ ⚠ same residue
ART4 p.Leu208= Benign same condition
ART4 p.Leu300Val Benign same condition
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

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-tyr126 (accessed [today's date]).

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