Is ACSL3 p.Ser668Pro (c.2002T>C) pathogenic?

ACSL3 p.Ser668Pro (c.2002T>C) is classified Uncertain significance in ACSL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). AlphaMissense: ambiguous (0.3517); Very rare (popmax 8.49e-05%, nfe).

How common is ACSL3 p.Ser668Pro (c.2002T>C) in the general population?

ACSL3 p.Ser668Pro (c.2002T>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about ACSL3 p.Ser668Pro (c.2002T>C)?

AlphaMissense predicts ambiguous (score 0.3517) — an in-silico prediction, not a clinical call.

ACSL3 p.Ser668Pro

c.2002T>C · VCV3482403

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3517 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3517	ambiguous
REVEL	0.194	benign-leaning
SaProt	LLR -9.88	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 20 kb · p 6.6e-15 · regional, not allelic
Overall
CADD	24.3	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 8.49e-05% European (non-Finnish) · 1/1,177,980 alleles

Overall 6.87e-05% 1/1,455,234 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.Ser668Pro
Coding: c.2002T>C
MANE Select: NM_004457
Type: single nucleotide variant
Location: chr2:222934684 (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 type
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.Ala176Val Uncertain significance ★ ⚠ same type
ACSL3 p.Ala201Thr Uncertain significance ★ ⚠ same type
ACSL3 p.Ala544Thr 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-ser668pro (accessed [today's date]).

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