Is ABCB4 p.Arg652Gly (c.1954A>G) pathogenic?

ABCB4 p.Arg652Gly (c.1954A>G) is classified Benign/Likely benign in ABCB4 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-04-14). AlphaMissense: likely benign (0.0667); Common (popmax 35%, afr) — too common for a highly-penetrant pathogenic allele; Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB4 p.Arg652Gly (c.1954A>G)?

ABCB4 p.Arg652Gly (c.1954A>G) is associated with familial intrahepatic cholestasis, gallbladder disease 1, progressive familial intrahepatic cholestasis type 3 (ClinVar).

What do computational predictors say about ABCB4 p.Arg652Gly (c.1954A>G)?

AlphaMissense predicts likely benign (score 0.0667) — an in-silico prediction, not a clinical call.

ABCB4 p.Arg652Gly

Q: How common is ABCB4 p.Arg652Gly (c.1954A>G) in the general population?

ABCB4 p.Arg652Gly (c.1954A>G) is common (popmax 35%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1954A>G · rs2230028 · VCV256160

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0667 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 35%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.0667	likely benign
REVEL	0.226	benign-leaning
SaProt	LLR -5.72	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 -0.41	GERP -2.4
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.53 · regional, not allelic
Overall
CADD	8.552	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 35% African / African-American · 26,197/74,876 alleles

Filtering AF 34.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 34.5%

Overall 8.95% 144,410/1,613,710 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	35%	3
South Asian	13.6%	7
Remaining individualsnot grpmax-eligible	9.58%	10
Admixed American	9.25%	11
Ashkenazi Jewishnot grpmax-eligible	9.21%	11
Amishnot grpmax-eligible	9.21%	11
Middle Eastern	8.08%	12
Finnishnot grpmax-eligible	7.36%	14
European (non-Finnish)	7.23%	14
East Asian	2.3%	43

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.Arg652Gly
Coding: c.1954A>G
MANE Select: NM_000443
dbSNP: rs2230028
Type: single nucleotide variant
Location: chr7:87426860 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 652: a UniProt-annotated variant site (in)

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

Disease context

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

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

Similar variants

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
ABCB4 c.3081+1G>C 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-arg652gly (accessed [today's date]).

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