Is ABCB4 p.Arg582Gln (c.1745G>A) pathogenic?

ABCB4 p.Arg582Gln (c.1745G>A) is classified Conflicting classifications of pathogenicity in ABCB4 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-04-14). AlphaMissense: likely benign (0.2142); Very rare (popmax 0.000424%, nfe); Associated with ABCB4-related disorder.

What condition is associated with ABCB4 p.Arg582Gln (c.1745G>A)?

ABCB4 p.Arg582Gln (c.1745G>A) is associated with ABCB4-related disorder, progressive familial intrahepatic cholestasis type 1, gallbladder disease 1 (ClinVar).

How common is ABCB4 p.Arg582Gln (c.1745G>A) in the general population?

ABCB4 p.Arg582Gln (c.1745G>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about ABCB4 p.Arg582Gln (c.1745G>A)?

AlphaMissense predicts likely benign (score 0.2142) — an in-silico prediction, not a clinical call.

ABCB4 p.Arg582Gln

c.1745G>A · rs760153272 · VCV802327

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2142 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCB4-related disorder

Computational evidence

Protein change
AlphaMissense	0.2142	likely benign
REVEL	0.787	moderately pathogenic-leaning
SaProt	LLR -13.99	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	28.5	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 0.000424% European (non-Finnish) · 5/1,179,948 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,892 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,480
Finnishnot grpmax-eligible	0.00156%	64,014
European (non-Finnish)grpmax	0.000424%	235,990

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.Arg582Gln
Coding: c.1745G>A
MANE Select: NM_000443
dbSNP: rs760153272
Type: single nucleotide variant
Location: chr7:87431552 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 582: the abc transporter 1 domain

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

Disease context

ABCB4-related disorder

Also linked: progressive familial intrahepatic cholestasis type 1 gallbladder disease 1 progressive familial intrahepatic cholestasis type 3 cholestasis, intrahepatic, of pregnancy, 3 familial intrahepatic cholestasis

Similar variants

ABCB4 p.Arg582Trp Conflicting classifications of pathogenicity ★ ⚠ 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
ABCB4 c.286+1G>A 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-arg582gln (accessed [today's date]).

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