Is ABCB4 p.Ala562Val (c.1685C>T) pathogenic?

ABCB4 p.Ala562Val (c.1685C>T) is classified Uncertain significance in ABCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-14). AlphaMissense: likely pathogenic (0.873); Very rare (popmax 8.47e-05%, nfe); Associated with gallbladder disease 1.

What condition is associated with ABCB4 p.Ala562Val (c.1685C>T)?

ABCB4 p.Ala562Val (c.1685C>T) is associated with gallbladder disease 1 (ClinVar).

How common is ABCB4 p.Ala562Val (c.1685C>T) in the general population?

ABCB4 p.Ala562Val (c.1685C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Low phospholipid-associated cholelithiasis inherited?

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

What do computational predictors say about ABCB4 p.Ala562Val (c.1685C>T)?

AlphaMissense predicts likely pathogenic (score 0.873) — an in-silico prediction, not a clinical call.

ABCB4 p.Ala562Val

c.1685C>T · VCV4846400

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

gallbladder disease 1

Computational evidence

Protein change
AlphaMissense	0.873	likely pathogenic
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -14.94	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · 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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,006 alleles

Overall 0.000137% 2/1,461,878 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)grpmax	8.47e-05%	1,180,006

Remaining individuals 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: ABCB4
Protein: p.Ala562Val
Coding: c.1685C>T
MANE Select: NM_000443
Type: single nucleotide variant
Location: chr7:87439713 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 562: the abc transporter 1 domain

Full ABCB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

gallbladder disease 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Low phospholipid-associated cholelithiasis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult

Similar variants

ABCB4 p.Ala562= Likely benign ★★ same residue
ABCB4 c.1356+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.2211+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.2682+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.286+1G>A Pathogenic ★★ same condition
ABCB4 c.3486+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.3486+5G>A Likely pathogenic ★★ same condition
ABCB4 c.80+1G>A 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/abcb4-p-ala562val (accessed [today's date]).

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