Is ACSL4 p.Pro334Leu (c.1001C>T) pathogenic?

ACSL4 p.Pro334Leu (c.1001C>T) is classified Likely pathogenic in ACSL4 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-01-02). AlphaMissense: likely pathogenic (0.9974); Very rare (popmax 0.00217%, amr); Associated with intellectual disability, X-linked 63.

What condition is associated with ACSL4 p.Pro334Leu (c.1001C>T)?

ACSL4 p.Pro334Leu (c.1001C>T) is associated with intellectual disability, X-linked 63 (ClinVar).

How common is ACSL4 p.Pro334Leu (c.1001C>T) in the general population?

ACSL4 p.Pro334Leu (c.1001C>T) is very rare (popmax 0.00217%, amr) (gnomAD).

What do computational predictors say about ACSL4 p.Pro334Leu (c.1001C>T)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

ACSL4 p.Pro334Leu

c.1001C>T · rs122458139 · VCV11566

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00217%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, X-linked 63

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic ✓ concordant with ClinVar · top 4% in ACSL4
REVEL	0.742	pathogenic-leaning
SaProt	LLR -17.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 34 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	33.0	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 P375L vs ClinVar P334L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00217% Admixed American · 1/46,048 alleles

Overall 0.000184% 2/1,085,808 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00217%	46,048
European (non-Finnish)	0.000113%	884,314

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.Pro334Leu
Coding: c.1001C>T
MANE Select: NM_001318510
dbSNP: rs122458139
Type: single nucleotide variant
Location: chrX:109674403 (GRCh38)
Structure: AlphaFold pLDDT 90.46

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

Disease context

intellectual disability, X-linked 63 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACSL4 p.Pro334fs Uncertain significance ★ same residue
ACSL4 p.Arg631Gln Uncertain significance ★★ ⚠ same condition
ACSL4 p.Asp521Asn Uncertain significance ★★ ⚠ same condition
ACSL4 p.His23Arg Uncertain significance ★★ ⚠ same condition
ACSL4 p.Lys271Arg Uncertain significance ★★ ⚠ same condition
ACSL4 p.Lys388Arg Uncertain significance ★★ ⚠ same condition
ACSL4 p.Ser501Tyr Uncertain significance ★★ ⚠ same condition
ACSL4 c.1697+31G>A 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-pro334leu (accessed [today's date]).

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