Is ACSL4 p.Glu494Asp (c.1482G>C) pathogenic?

ACSL4 p.Glu494Asp (c.1482G>C) is classified Uncertain significance in ACSL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-21). AlphaMissense: likely benign (0.1017); Very rare (popmax 0.00217%, amr).

How common is ACSL4 p.Glu494Asp (c.1482G>C) in the general population?

ACSL4 p.Glu494Asp (c.1482G>C) is very rare (popmax 0.00217%, amr) (gnomAD).

What do computational predictors say about ACSL4 p.Glu494Asp (c.1482G>C)?

AlphaMissense predicts likely benign (score 0.1017) — an in-silico prediction, not a clinical call.

ACSL4 p.Glu494Asp

c.1482G>C · rs1258779115 · VCV2446218

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1017 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00217%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1017	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -10.06	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.1	GERP 0.94, phastCons 0.92
Regional constraint	o/e 0.63	unconstrained · MANE · 34 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	16.67	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 E535D vs ClinVar E494D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00217% Admixed American · 1/45,978 alleles

Filtering AF 8.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000365% 4/1,095,650 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00217%	45,978
European (non-Finnish)	0.000336%	297,784

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.Glu494Asp
Coding: c.1482G>C
MANE Select: NM_001318510
dbSNP: rs1258779115
Type: single nucleotide variant
Location: chrX:109663311 (GRCh38)
Structure: AlphaFold pLDDT 90.46

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

Similar variants

ACSL4 p.Arg631Gln Uncertain significance ★★ ⚠ same type
ACSL4 p.Asn95Asp Uncertain significance ★★ ⚠ same type
ACSL4 p.Asn95Ser Uncertain significance ★★ ⚠ same type
ACSL4 p.Asp521Asn Uncertain significance ★★ ⚠ same type
ACSL4 p.His150Leu Uncertain significance ★★ ⚠ same type
ACSL4 p.His23Arg Uncertain significance ★★ ⚠ same type
ACSL4 p.Lys271Arg Uncertain significance ★★ ⚠ same type
ACSL4 p.Lys388Arg 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/acsl4-p-glu494asp (accessed [today's date]).

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