Is ABCG5 p.Ala466Val (c.1397C>T) pathogenic?

ABCG5 p.Ala466Val (c.1397C>T) is classified Uncertain significance in ABCG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: ambiguous (0.3605); Very rare (popmax 0.00769%, sas).

How common is ABCG5 p.Ala466Val (c.1397C>T) in the general population?

ABCG5 p.Ala466Val (c.1397C>T) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about ABCG5 p.Ala466Val (c.1397C>T)?

AlphaMissense predicts ambiguous (score 0.3605) — an in-silico prediction, not a clinical call.

ABCG5 p.Ala466Val

c.1397C>T · VCV4085360

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3605 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3605	ambiguous
REVEL	0.751	pathogenic-leaning
SaProt	LLR -9.64	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	27.8	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 0.00769% South Asian · 7/91,062 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000479% 7/1,461,862 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: ABCG5
Protein: p.Ala466Val
Coding: c.1397C>T
MANE Select: NM_022436
Type: single nucleotide variant
Location: chr2:43822863 (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

Similar variants

ABCG5 p.Ala466= Conflicting classifications of pathogenicity ★ same residue
ABCG5 p.Ala466Pro Uncertain significance ★ ⚠ same residue
ABCG5 c.1325-1G>T Likely pathogenic ★★ same type
ABCG5 c.1464-1G>C Pathogenic/Likely pathogenic ★★ same type
ABCG5 c.1762+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCG5 c.634+1G>C Likely pathogenic ★★ same type
ABCG5 c.904+1G>A Pathogenic ★★ same type
ABCG5 p.Arg183Ter Pathogenic/Likely pathogenic ★★ 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/abcg5-p-ala466val (accessed [today's date]).

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