Is ABCB4 p.Arg595Gln (c.1784G>A) pathogenic?

ABCB4 p.Arg595Gln (c.1784G>A) is classified Uncertain significance in ABCB4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-08). AlphaMissense: likely benign (0.0929); Ultra-rare (popmax 0.0534%, afr); Associated with cholestasis, intrahepatic, of pregnancy, 3.

What condition is associated with ABCB4 p.Arg595Gln (c.1784G>A)?

ABCB4 p.Arg595Gln (c.1784G>A) is associated with cholestasis, intrahepatic, of pregnancy, 3, progressive familial intrahepatic cholestasis type 3 (ClinVar).

How common is ABCB4 p.Arg595Gln (c.1784G>A) in the general population?

ABCB4 p.Arg595Gln (c.1784G>A) is ultra-rare (popmax 0.0534%, afr) (gnomAD).

How is Intrahepatic cholestasis of pregnancy inherited?

Typically Multigenic/multifactorial, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCB4 p.Arg595Gln (c.1784G>A)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

ABCB4 p.Arg595Gln

c.1784G>A · rs144398632 · VCV360801

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0534%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cholestasis, intrahepatic, of pregnancy, 3

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.386	indeterminate
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.53 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0534% African / African-American · 40/74,916 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0357%

Overall 0.00551% 89/1,614,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0534%	1,873
Remaining individualsnot grpmax-eligible	0.0096%	10,414
Finnishnot grpmax-eligible	0.00468%	21,345
European (non-Finnish)	0.00322%	31,053
South Asian	0.0022%	45,541

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.Arg595Gln
Coding: c.1784G>A
MANE Select: NM_000443
dbSNP: rs144398632
Type: single nucleotide variant
Location: chr7:87431513 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 595: the abc transporter 1 domain

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

Disease context

cholestasis, intrahepatic, of pregnancy, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: progressive familial intrahepatic cholestasis type 3

For Intrahepatic cholestasis of pregnancy (Orphanet):

Inheritance: Multigenic/multifactorial, Not applicable
Onset: Adult

Similar variants

ABCB4 p.Arg595Ter Pathogenic ★★ same residue
ABCB4 p.Arg595Gly Uncertain significance ★ same residue
ABCB4 c.1560+1G>A 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.3081+1G>C Pathogenic ★★ same condition
ABCB4 c.3486+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.834-1G>A 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-arg595gln (accessed [today's date]).

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