Is ACSL3 p.Ala176Val (c.527C>T) pathogenic?

ACSL3 p.Ala176Val (c.527C>T) is classified Uncertain significance in ACSL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: ambiguous (0.3518); Very rare (popmax 0.00017%, nfe).

How common is ACSL3 p.Ala176Val (c.527C>T) in the general population?

ACSL3 p.Ala176Val (c.527C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about ACSL3 p.Ala176Val (c.527C>T)?

AlphaMissense predicts ambiguous (score 0.3518) — an in-silico prediction, not a clinical call.

ACSL3 p.Ala176Val

c.527C>T · VCV4219049

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3518 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3518	ambiguous
REVEL	0.289	benign-leaning
SaProt	LLR -11.34	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.35	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 13 kb · p 0.44 · 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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,178,802 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,459,370 alleles · very rare

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: ACSL3
Protein: p.Ala176Val
Coding: c.527C>T
MANE Select: NM_004457
Type: single nucleotide variant
Location: chr2:222916467 (GRCh38)
Gene constraint: LOEUF 0.605 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.79

Full ACSL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACSL3 p.Ala176= Benign ★★ same residue
ACSL3 p.Lys265Arg Likely benign ★★ ⚠ same type
ACSL3 p.Lys630= Benign ★★ same type
ACSL3 p.Thr11= Benign/Likely benign ★★ same type
ACSL3 p.Ala163Ser Uncertain significance ★ ⚠ same type
ACSL3 p.Ala201Thr Uncertain significance ★ ⚠ same type
ACSL3 p.Ala544Thr Uncertain significance ★ ⚠ same type
ACSL3 p.Ala599Val 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/acsl3-p-ala176val (accessed [today's date]).

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