Is ACSL4 p.Pro472Ala (c.1414C>G) pathogenic?

ACSL4 p.Pro472Ala (c.1414C>G) is classified Uncertain significance in ACSL4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-05-27). AlphaMissense: ambiguous (0.5437); Very rare (popmax 0.00525%, afr).

How common is ACSL4 p.Pro472Ala (c.1414C>G) in the general population?

ACSL4 p.Pro472Ala (c.1414C>G) is very rare (popmax 0.00525%, afr) (gnomAD).

What do computational predictors say about ACSL4 p.Pro472Ala (c.1414C>G)?

AlphaMissense predicts ambiguous (score 0.5437) — an in-silico prediction, not a clinical call.

ACSL4 p.Pro472Ala

c.1414C>G · rs375616665 · VCV1299444

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5437 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00525%, afr)

Computational evidence

Protein change
AlphaMissense	0.5437	ambiguous
REVEL	0.431	indeterminate
SaProt	LLR -15.37	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 34 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	24.5	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 P513A vs ClinVar P472A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00525% African / African-American · 3/57,122 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0011%

Overall 0.0019% 23/1,207,658 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00525%	19,041
Admixed American	0.00219%	45,620
European (non-Finnish)	0.00213%	47,017

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.Pro472Ala
Coding: c.1414C>G
MANE Select: NM_001318510
dbSNP: rs375616665
Type: single nucleotide variant
Location: chrX:109663379 (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-pro472ala (accessed [today's date]).

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