Is ABCB4 p.Glu528Asp (c.1584G>C) pathogenic?

ABCB4 p.Glu528Asp (c.1584G>C) is classified Benign/Likely benign in ABCB4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-04-14). AlphaMissense: likely benign (0.1229); Low-frequency (popmax 2.89%, afr); Associated with gallbladder disease 1.

What condition is associated with ABCB4 p.Glu528Asp (c.1584G>C)?

ABCB4 p.Glu528Asp (c.1584G>C) is associated with gallbladder disease 1, progressive familial intrahepatic cholestasis type 3, cholestasis, intrahepatic, of pregnancy, 3 (ClinVar).

How common is ABCB4 p.Glu528Asp (c.1584G>C) in the general population?

ABCB4 p.Glu528Asp (c.1584G>C) is low-frequency (popmax 2.89%, afr) (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.Glu528Asp (c.1584G>C)?

AlphaMissense predicts likely benign (score 0.1229) — an in-silico prediction, not a clinical call.

ABCB4 p.Glu528Asp

c.1584G>C · rs8187797 · VCV194334

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1229 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.89%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

gallbladder disease 1

Computational evidence

Protein change
AlphaMissense	0.1229	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -3.7
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	4.862	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 2.89% African / African-American · 2,172/75,030 alleles

Filtering AF 2.79% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.75%

Overall 0.151% 2,444/1,614,180 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.89%	35
Remaining individualsnot grpmax-eligible	0.178%	563
Middle Eastern	0.165%	606
Admixed American	0.157%	639
South Asian	0.0132%	7,590
European (non-Finnish)	0.00381%	26,223

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.Glu528Asp
Coding: c.1584G>C
MANE Select: NM_000443
dbSNP: rs8187797
Type: single nucleotide variant
Location: chr7:87439814 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 528: an α-helix; the abc transporter 1 domain; a UniProt-annotated variant site (in gbd1; uncertain significance; moderate decrease of phosphatidylcholine transporter activity; does not alter plasma membrane location)

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

Also linked: progressive familial intrahepatic cholestasis type 3 cholestasis, intrahepatic, of pregnancy, 3 familial intrahepatic cholestasis

For Low phospholipid-associated cholelithiasis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult

Similar variants

ABCB4 p.Glu528fs Pathogenic ★ same residue
CROT p.Pro528Ala Uncertain significance ★ ⚠ same residue
ABCB4 c.1356+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.1560+1G>A Likely pathogenic ★★ same condition
ABCB4 c.2064+3A>T 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.2783+1G>T 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/abcb4-p-glu528asp (accessed [today's date]).

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