Is ACSL4 p.Leu367Ser (c.1100T>C) pathogenic?

ACSL4 p.Leu367Ser (c.1100T>C) is classified Uncertain significance in ACSL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-14). AlphaMissense: ambiguous (0.4491); Very rare (popmax 0.00174%, afr).

How common is ACSL4 p.Leu367Ser (c.1100T>C) in the general population?

ACSL4 p.Leu367Ser (c.1100T>C) is very rare (popmax 0.00174%, afr) (gnomAD).

What do computational predictors say about ACSL4 p.Leu367Ser (c.1100T>C)?

AlphaMissense predicts ambiguous (score 0.4491) — an in-silico prediction, not a clinical call.

ACSL4 p.Leu367Ser

c.1100T>C · rs966241966 · VCV2502074

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4491 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00174%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4491	ambiguous
REVEL	0.269	benign-leaning
SaProt	LLR -7.42	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 34 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	25.9	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 L408S vs ClinVar L367S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00174% African / African-American · 1/57,505 alleles

Overall 9.22e-05% 1/1,085,077 alleles · very rare

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.Leu367Ser
Coding: c.1100T>C
MANE Select: NM_001318510
dbSNP: rs966241966
Type: single nucleotide variant
Location: chrX:109669076 (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-leu367ser (accessed [today's date]).

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