Is ABCB4 p.Arg788Leu (c.2363G>T) pathogenic?

ABCB4 p.Arg788Leu (c.2363G>T) is classified Uncertain significance in ABCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-14). AlphaMissense: likely pathogenic (0.9241); Very rare (popmax 0.00988%, sas); Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB4 p.Arg788Leu (c.2363G>T)?

ABCB4 p.Arg788Leu (c.2363G>T) is associated with familial intrahepatic cholestasis, gallbladder disease 1 (ClinVar).

How common is ABCB4 p.Arg788Leu (c.2363G>T) in the general population?

ABCB4 p.Arg788Leu (c.2363G>T) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about ABCB4 p.Arg788Leu (c.2363G>T)?

AlphaMissense predicts likely pathogenic (score 0.9241) — an in-silico prediction, not a clinical call.

ABCB4 p.Arg788Leu

c.2363G>T · VCV4846609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9241 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.9241	likely pathogenic
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -12.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.99, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.53 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00988% South Asian · 9/91,080 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.000752% 11/1,461,806 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,120
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)	8.47e-05%	1,179,960

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.Arg788Leu
Coding: c.2363G>T
MANE Select: NM_000443
Type: single nucleotide variant
Location: chr7:87420029 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 788: a UniProt-annotated variant site (in gbd1; benign); an α-helix; the abc transmembrane type-1 2 domain

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

Similar variants

ABCB4 p.Arg788Trp Uncertain significance ★★ ⚠ same residue
ABCB4 p.Arg788Gln Benign/Likely benign ★★ same residue
ABCB4 c.1356+2T>C Pathogenic/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-arg788leu (accessed [today's date]).

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