Is ACSL4 p.Ile421Val (c.1261A>G) pathogenic?

ACSL4 p.Ile421Val (c.1261A>G) is classified Likely benign in ACSL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-07). AlphaMissense: likely benign (0.0494); Very rare (popmax 0.00875%, amr); Associated with Inborn genetic diseases.

What condition is associated with ACSL4 p.Ile421Val (c.1261A>G)?

ACSL4 p.Ile421Val (c.1261A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ACSL4 p.Ile421Val (c.1261A>G) in the general population?

ACSL4 p.Ile421Val (c.1261A>G) is very rare (popmax 0.00875%, amr) (gnomAD).

What do computational predictors say about ACSL4 p.Ile421Val (c.1261A>G)?

AlphaMissense predicts likely benign (score 0.0494) — an in-silico prediction, not a clinical call.

ACSL4 p.Ile421Val

c.1261A>G · VCV3825336

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0494 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00875%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0494	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -6.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP -3.6, phastCons 0.009
Regional constraint	o/e 0.63	unconstrained · MANE · 34 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	2.084	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 I462V vs ClinVar I421V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00875% Admixed American · 4/45,702 alleles

Filtering AF 0.00294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00364% 44/1,207,594 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0105%	9,503
Admixed Americangrpmax	0.00875%	11,426
African / African-American	0.00701%	14,256
European (non-Finnish)	0.00347%	28,816

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile421Val
Coding: c.1261A>G
MANE Select: NM_001318510
Type: single nucleotide variant
Location: chrX:109668155 (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.Ile421Thr Uncertain significance ★ 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-ile421val (accessed [today's date]).

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