Is ABCG5 p.Ala466Pro (c.1396G>C) pathogenic?

ABCG5 p.Ala466Pro (c.1396G>C) is classified Uncertain significance in ABCG5 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.8419); Absent from gnomAD v4.1; Associated with sitosterolemia 2.

What condition is associated with ABCG5 p.Ala466Pro (c.1396G>C)?

ABCG5 p.Ala466Pro (c.1396G>C) is associated with sitosterolemia 2 (ClinVar).

How common is ABCG5 p.Ala466Pro (c.1396G>C) in the general population?

ABCG5 p.Ala466Pro (c.1396G>C) is absent from gnomAD v4.1 (gnomAD).

How is Sitosterolemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCG5 p.Ala466Pro (c.1396G>C)?

AlphaMissense predicts likely pathogenic (score 0.8419) — an in-silico prediction, not a clinical call.

ABCG5 p.Ala466Pro

c.1396G>C · VCV4279000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8419 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sitosterolemia 2

Computational evidence

Protein change
AlphaMissense	0.8419	likely pathogenic · top 9% in ABCG5
REVEL	0.739	pathogenic-leaning
SaProt	LLR -12.91	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCG5
Protein: p.Ala466Pro
Coding: c.1396G>C
MANE Select: NM_022436
Type: single nucleotide variant
Location: chr2:43822864 (GRCh38)
Gene constraint: LOEUF 1.219 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 8 PDB
Residue 466: the abc transmembrane type-2 domain; an α-helix

Full ABCG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sitosterolemia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sitosterolemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

ABCG5 p.Ala466= Conflicting classifications of pathogenicity ★ same residue
ABCG5 p.Ala466Val Uncertain significance ★ ⚠ same residue
ABCG5 c.1464-1G>C Pathogenic/Likely pathogenic ★★ same condition
ABCG5 c.1762+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCG5 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG5 p.Arg243Ter Pathogenic ★★ same condition
ABCG5 p.Arg389His Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCG5 p.Arg408Ter Pathogenic/Likely pathogenic ★★ 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/abcg5-p-ala466pro (accessed [today's date]).

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