Is ACSL4 p.Arg92Cys (c.274C>T) pathogenic?

ACSL4 p.Arg92Cys (c.274C>T) is classified Likely benign in ACSL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1049); Ultra-rare (popmax 0.0686%, mid); Associated with Inborn genetic diseases.

What condition is associated with ACSL4 p.Arg92Cys (c.274C>T)?

ACSL4 p.Arg92Cys (c.274C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACSL4 p.Arg92Cys (c.274C>T) in the general population?

ACSL4 p.Arg92Cys (c.274C>T) is ultra-rare (popmax 0.0686%, mid) (gnomAD).

What do computational predictors say about ACSL4 p.Arg92Cys (c.274C>T)?

AlphaMissense predicts likely benign (score 0.1049) — an in-silico prediction, not a clinical call.

ACSL4 p.Arg92Cys

c.274C>T · VCV4566075

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1049 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0686%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1049	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -11.08	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Pangolin	Δ0.20	loss · gain 0.11 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP -0.044	GERP -3.9
Regional constraint	o/e 0.78	unconstrained · MANE · 5,257 bp · p 0.0019 · regional, not allelic
Overall
CADD	7.275	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R133C vs ClinVar R92C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0686% Middle Eastern · 3/4,376 alleles

Filtering AF 0.0186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00991%

Overall 0.00107% 13/1,209,406 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0686%	1,459
South Asian	0.0123%	8,118
East Asian	0.00592%	16,891
European (non-Finnish)	0.000112%	894,678

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: ACSL4
Protein: p.Arg92Cys
Coding: c.274C>T
MANE Select: NM_001318510
Type: single nucleotide variant
Location: chrX:109682851 (GRCh38)
Structure: AlphaFold pLDDT 90.46

Full ACSL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACSL4 p.Arg92His Conflicting classifications of pathogenicity ★ ⚠ same residue
ACSL4 p.Asn95Asp Uncertain significance ★★ ⚠ same condition
ACSL4 p.Asn95Ser Uncertain significance ★★ ⚠ same condition
ACSL4 p.His23Arg Uncertain significance ★★ ⚠ same condition
ACSL4 p.Pro404Leu Uncertain significance ★★ ⚠ same condition
ACSL4 p.Ser501Tyr Uncertain significance ★★ ⚠ same condition
ACSL4 p.Tyr132Cys Uncertain significance ★★ ⚠ same condition
ACSL4 p.Asn153Ser Benign/Likely benign ★★ ⚠ same condition

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/acsl4-p-arg92cys (accessed [today's date]).

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