Is ACOX2 p.Pro61Leu (c.182C>T) pathogenic?

ACOX2 p.Pro61Leu (c.182C>T) is classified Likely benign in ACOX2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-21). AlphaMissense: likely benign (0.1833); Rare (popmax 0.292%, afr); Associated with congenital bile acid synthesis defect 6.

What condition is associated with ACOX2 p.Pro61Leu (c.182C>T)?

ACOX2 p.Pro61Leu (c.182C>T) is associated with congenital bile acid synthesis defect 6 (ClinVar).

How common is ACOX2 p.Pro61Leu (c.182C>T) in the general population?

ACOX2 p.Pro61Leu (c.182C>T) is rare (popmax 0.292%, afr) (gnomAD).

What do computational predictors say about ACOX2 p.Pro61Leu (c.182C>T)?

AlphaMissense predicts likely benign (score 0.1833) — an in-silico prediction, not a clinical call.

ACOX2 p.Pro61Leu

c.182C>T · rs149303910 · VCV1301652

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1833 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.292%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital bile acid synthesis defect 6

Computational evidence

Protein change
AlphaMissense	0.1833	likely benign
REVEL	0.34	indeterminate
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 30 kb · p 0.14 · regional, not allelic
Overall
CADD	24.7	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 0.292% African / African-American · 219/75,020 alleles

Filtering AF 0.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.248%

Overall 0.016% 259/1,614,138 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.292%	343
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.024%	4,167
Admixed American	0.0167%	6,002
South Asian	0.00549%	18,216
East Asian	0.00223%	44,876
European (non-Finnish)	0.000593%	168,575

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.Pro61Leu
Coding: c.182C>T
MANE Select: NM_003500
dbSNP: rs149303910
Type: single nucleotide variant
Location: chr3:58534501 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.49

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

Disease context

congenital bile acid synthesis defect 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACOX2 c.161-57C>G Benign ★★ same condition
ACOX2 c.475+18C>T Benign/Likely benign ★★ same condition
ACOX2 c.-26T>C Benign ★★ same condition
ACOX2 p.Arg225Gln Likely pathogenic ★ same condition
ACOX2 c.1983+2T>C Uncertain significance ★ same condition
ACOX2 c.323+2T>C Conflicting classifications of pathogenicity ★ same condition
ACOX2 p.Arg127Lys Uncertain significance ★ ⚠ same condition
ACOX2 p.Arg225Trp Conflicting classifications of pathogenicity ★ ⚠ same condition

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-pro61leu (accessed [today's date]).

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