ABCB4

Chr 7ADAR

ATP binding cassette subfamily B member 4

Also known as: ABC21, GBD1, ICP3, MDR2, MDR2/3, MDR3, PFIC-3, PGY3

NCBI Gene: 5244ENSG00000005471UniProt: P21439

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This gene encodes a full transporter and member of the p-glycoprotein family of membrane proteins with phosphatidylcholine as its substrate. The function of this protein has not yet been determined; however, it may involve transport of phospholipids from liver hepatocytes into bile. Alternative splicing of this gene results in several products of undetermined function. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Cholestasis, intrahepatic, of pregnancy, 3MIM #614972
ADAR
Cholestasis, progressive familial intrahepatic 3MIM #602347
AR
Gallbladder disease 1MIM #600803
ADAR
UniProtCholestasis of pregnancy, intrahepatic 3
631
ClinVar variants
108
Pathogenic / LP
0.00
pLI score
3
Active trials
Clinical Summary— ABCB4
🧬
Gene-Disease Validity (ClinGen)
progressive familial intrahepatic cholestasis type 3 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
108 Pathogenic / Likely Pathogenic· 362 VUS of 631 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.51LOEUF
pLI 0.000
Z-score 4.82
OE 0.36 (0.26–0.51)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.97Z-score
OE missense 0.79 (0.73–0.85)
539 obs / 684.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.36 (0.26–0.51)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.73–0.85)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.93
0≤1.21.6
LoF obs/exp: 24 / 66.4Missense obs/exp: 539 / 684.4Syn Z: 0.83

ClinVar Variant Classifications

631 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55
Likely Pathogenic53
VUS362
Likely Benign79
Benign25
Conflicting57
55
Pathogenic
53
Likely Pathogenic
362
VUS
79
Likely Benign
25
Benign
57
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
26
3
26
0
55
Likely Pathogenic
20
19
14
0
53
VUS
3
326
24
9
362
Likely Benign
0
11
32
36
79
Benign
0
0
20
5
25
Conflicting
—57
Total4935911650631

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ABCB4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cholestasis, intrahepatic, of pregnancy, 3

MIM #614972

Molecular basis of disorder known

Autosomal dominantAutosomal recessive

Cholestasis, progressive familial intrahepatic 3

MIM #602347

Molecular basis of disorder known

Autosomal recessive

Gallbladder disease 1

MIM #600803

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
📖
GeneReview available — ABCB4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Molecular overview of progressive familial intrahepatic cholestasis.
Amirneni S et al.·World J Gastroenterol
2020Review
Low-Phospholipid Associated Cholelithiasis (LPAC) syndrome: A synthetic review.
Goubault P et al.·J Visc Surg
2019Review
Systematic review of progressive familial intrahepatic cholestasis.
Baker A et al.·Clin Res Hepatol Gastroenterol
2019Review
Clinical phenotype of adult-onset liver disease in patients with variants in ABCB4, ABCB11, and ATP8B1.
Nayagam JS et al.·Hepatol Commun
2022Cohort
Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases.
Chen HL et al.·J Biomed Sci
2018Review
Cholestatic liver disease.
Jüngst C et al.·Dig Dis
2013Review
Bile acids engage the SIPR-STAT3 signaling axis to modulate regulatory T cell responses in fibrosing cholangiopathies.
Kudira R et al.·J Hepatol
2025
ABCB4 disease: Many faces of one gene deficiency.
Sticova E et al.·Ann Hepatol
2020Review
Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis.
Wang HH et al.·Genes (Basel)
2022Review
Molecular Advances in Cholestatic Liver Diseases.
Memon R et al.·Adv Anat Pathol
2025Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Molecular characterisation of the trafficking rescue of defective ABCB4 variants by roscovitine analogues.
Banet M et al.·Sci Rep
2026
A Rare Nonsense Mutation in the ABCB4 Gene Associated with Progressive Familial Intrahepatic Cholestasis Type 3: A Case Report.
Cai B et al.·J Clin Med
2026🔓 Open AccessCase report
Clinical spectrum and genotype-phenotype correlation of ABCB4 mutations in children: Insights from a North Indian cohort.
Thunga C et al.·World J Hepatol
2026🔓 Open AccessCohort
ABCB4 disease-causing variants S242R, S346I, T437I and T1077M significantly impair its function and display differential sensitivity to potentiators.
Madry C et al.·Sci Rep
2025🔓 Open Access
Leukemia inhibitory factor promotes human cholangiopathies, and its inhibition improves cholestasis in Abcb4-/- mice.
Di Giorgio C et al.·Hepatol Commun
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
PFIC - Progressive Familial Intrahepatic CholestasisAlagille Syndrome (ALGS)Cholestasis, Intrahepatic

Pediatric Evaluation and Registry for Liver Cholestasis in Canada

NOT YET RECRUITING
NCT07411716Children's Hospital of Eastern OntarioStarted 2026-03
Low Phospholipid Associated Cholelithiasis

COLPAC (RaDiCo Cohort) (RaDiCo-COLPAC)

ACTIVE NOT RECRUITING
NCT05961826Institut National de la Santé Et de la Recherche Médicale, FranceStarted 2017-11-06
Breast Cancer

Treating Breast Cancer Patients Undergoing Trastuzumab Treatment With Carvedilol to Reduce Incidence of Heart Failure

ACTIVE NOT RECRUITING
NCT03879629Phase PHASE2Mayo ClinicStarted 2019-08-21
Carvedilol

External Resources

Links to major genomics databases and tools