Is ACOX2 p.Ser211Leu (c.632C>T) pathogenic?

ACOX2 p.Ser211Leu (c.632C>T) is classified Conflicting classifications of pathogenicity in ACOX2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.1164); Ultra-rare (popmax 0.025%, amr).

How common is ACOX2 p.Ser211Leu (c.632C>T) in the general population?

ACOX2 p.Ser211Leu (c.632C>T) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about ACOX2 p.Ser211Leu (c.632C>T)?

AlphaMissense predicts likely benign (score 0.1164) — an in-silico prediction, not a clinical call.

ACOX2 p.Ser211Leu

c.632C>T · rs148493303 · VCV2377259

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1164 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1164	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -8.58	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 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 30 kb · p 0.14 · regional, not allelic
Overall
CADD	21.2	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 0.025% Admixed American · 15/60,012 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.016% 259/1,614,086 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.449%	223
Remaining individualsnot grpmax-eligible	0.0352%	2,840
Admixed Americangrpmax	0.025%	4,001
European (non-Finnish)	0.00737%	13,564
African / African-American	0.00267%	37,474

Ashkenazi Jewish 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: ACOX2
Protein: p.Ser211Leu
Coding: c.632C>T
MANE Select: NM_003500
dbSNP: rs148493303
Type: single nucleotide variant
Location: chr3:58531764 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.49
Residue 211: a UniProt-annotated variant site (in cbas6; patient liver samples show absence of the protein; complete loss of fatty acid beta-oxidation activity)

Full ACOX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOX2 p.Ser211Pro Uncertain significance ★ ⚠ same residue
ACOX2 p.Ala106Val Uncertain significance ★★ ⚠ same type
ACOX2 p.Ala48Glu Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg197Gln Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg197Trp Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg215Trp Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg318His Uncertain significance ★★ ⚠ same type
ACOX2 p.Arg323Cys 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/acox2-p-ser211leu (accessed [today's date]).

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