Is ACSL6 p.Phe442Cys (c.1325T>G) pathogenic?

ACSL6 p.Phe442Cys (c.1325T>G) is classified Uncertain significance in ACSL6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). AlphaMissense: likely pathogenic (0.7766); Ultra-rare (popmax 0.0233%, amr).

How common is ACSL6 p.Phe442Cys (c.1325T>G) in the general population?

ACSL6 p.Phe442Cys (c.1325T>G) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

What do computational predictors say about ACSL6 p.Phe442Cys (c.1325T>G)?

AlphaMissense predicts likely pathogenic (score 0.7766) — an in-silico prediction, not a clinical call.

ACSL6 p.Phe442Cys

c.1325T>G · rs764113174 · VCV3140135

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7766 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7766	likely pathogenic
REVEL	0.592	indeterminate
SaProt	LLR -13.39	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 57 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F417C vs ClinVar F442C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0233% Admixed American · 14/59,996 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00118% 19/1,614,030 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,285
Remaining individualsnot grpmax-eligible	0.0048%	20,830
European (non-Finnish)	0.000169%	590,012

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.Phe442Cys
Coding: c.1325T>G
MANE Select: NM_001009185
dbSNP: rs764113174
Type: single nucleotide variant
Location: chr5:131972737 (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

Similar variants

ACSL6 p.Ala418Ser Uncertain significance ★ ⚠ same type
ACSL6 p.Ala507Val Uncertain significance ★ ⚠ same type
ACSL6 p.Ala609Val Uncertain significance ★ ⚠ same type
ACSL6 p.Arg122Cys Uncertain significance ★ ⚠ same type
ACSL6 p.Arg122His Uncertain significance ★ ⚠ same type
ACSL6 p.Arg182Gln Uncertain significance ★ ⚠ same type
ACSL6 p.Arg212Cys Uncertain significance ★ ⚠ same type
ACSL6 p.Arg336Lys 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/acsl6-p-phe442cys (accessed [today's date]).

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