Is ACOX3 p.Ala157Ser (c.469G>T) pathogenic?

ACOX3 p.Ala157Ser (c.469G>T) is classified Uncertain significance in ACOX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-11). AlphaMissense: likely benign (0.1631); Ultra-rare (popmax 0.0164%, mid).

How common is ACOX3 p.Ala157Ser (c.469G>T) in the general population?

ACOX3 p.Ala157Ser (c.469G>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ACOX3 p.Ala157Ser (c.469G>T)?

AlphaMissense predicts likely benign (score 0.1631) — an in-silico prediction, not a clinical call.

ACOX3 p.Ala157Ser

c.469G>T · VCV3824754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1631 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1631	likely benign
REVEL	0.792	moderately pathogenic-leaning
SaProt	LLR -9.90	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.30	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 5.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 50 kb · p 0.53 · regional, not allelic
Overall
CADD	24.8	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00105% 17/1,613,926 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Finnishnot grpmax-eligible	0.00625%	16,003
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00134%	74,892
European (non-Finnish)	0.000847%	117,997

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: ACOX3
Protein: p.Ala157Ser
Coding: c.469G>T
MANE Select: NM_003501
Type: single nucleotide variant
Location: chr4:8414366 (GRCh38)
Gene constraint: LOEUF 1.114 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.43

Full ACOX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOX3 p.Ala28= Benign ★★ same type
ACOX3 p.Arg75= Likely benign ★★ same type
ACOX3 p.Ala207Thr Uncertain significance ★ ⚠ same type
ACOX3 p.Ala261Ser Uncertain significance ★ ⚠ same type
ACOX3 p.Ala261Thr Uncertain significance ★ ⚠ same type
ACOX3 p.Ala2Thr Uncertain significance ★ ⚠ same type
ACOX3 p.Ala2Val Uncertain significance ★ ⚠ same type
ACOX3 p.Ala361Thr 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/acox3-p-ala157ser (accessed [today's date]).

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