Is ACSL6 p.Val223Met (c.667G>A) pathogenic?

ACSL6 p.Val223Met (c.667G>A) is classified Uncertain significance in ACSL6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: ambiguous (0.4367); Very rare (popmax 0.00949%, nfe); Associated with ACSL6-related disorder.

What condition is associated with ACSL6 p.Val223Met (c.667G>A)?

ACSL6 p.Val223Met (c.667G>A) is associated with ACSL6-related disorder (ClinVar).

How common is ACSL6 p.Val223Met (c.667G>A) in the general population?

ACSL6 p.Val223Met (c.667G>A) is very rare (popmax 0.00949%, nfe) (gnomAD).

What do computational predictors say about ACSL6 p.Val223Met (c.667G>A)?

AlphaMissense predicts ambiguous (score 0.4367) — an in-silico prediction, not a clinical call.

ACSL6 p.Val223Met

c.667G>A · VCV3779024

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4367 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00949%, nfe)

Conditions

ACSL6-related disorder

Computational evidence

Protein change
AlphaMissense	0.4367	ambiguous
REVEL	0.347	indeterminate
SaProt	LLR -10.19	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 57 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	32.0	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 V198M vs ClinVar V223M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00949% European (non-Finnish) · 112/1,180,004 alleles

Filtering AF 0.00804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00752%

Overall 0.00756% 122/1,614,012 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,925
European (non-Finnish)grpmax	0.00949%	10,536
African / African-American	0.00267%	37,462
South Asian	0.0011%	91,086

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: ACSL6
Protein: p.Val223Met
Coding: c.667G>A
MANE Select: NM_001009185
Type: single nucleotide variant
Location: chr5:131988212 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.15

Full ACSL6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ACSL6-related disorder

Similar variants

ACSL6 p.Lys668Glu Uncertain significance ★ ⚠ same condition
ACSL6 c.865-8C>G Benign same condition
ACSL6 p.Ala152= Likely benign same condition
ACSL6 p.Arg412Cys Likely benign ⚠ same condition
ACSL6 p.Glu17= Likely benign same condition
ACSL6 p.Ile566= Benign same condition
ACSL6 p.Thr3= Likely benign same condition
ACSL6 p.Thr651Ala 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/acsl6-p-val223met (accessed [today's date]).

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