Is ABCB4 p.Leu724fs (c.2169dup) pathogenic?

ABCB4 p.Leu724fs (c.2169dup) is classified Pathogenic in ABCB4 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-04-14). Very rare (popmax 0.000169%, nfe); Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB4 p.Leu724fs (c.2169dup)?

ABCB4 p.Leu724fs (c.2169dup) is associated with familial intrahepatic cholestasis, progressive familial intrahepatic cholestasis type 3 (ClinVar).

How common is ABCB4 p.Leu724fs (c.2169dup) in the general population?

ABCB4 p.Leu724fs (c.2169dup) is very rare (popmax 0.000169%, nfe) (gnomAD).

ABCB4 p.Leu724fs

c.2169dup · rs387906529 · VCV13694

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 17 of 28
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.4	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,964 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000274% 4/1,461,802 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,251
European (non-Finnish)grpmax	0.000169%	589,981

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.Leu724fs
Coding: c.2169dup
MANE Select: NM_000443
dbSNP: rs387906529
Type: Duplication
Location: chr7:87423947 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 724: 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: progressive familial intrahepatic cholestasis type 3

Similar variants

ABCB4 c.3486+10dup Benign/Likely benign ★★ same condition
ABCB4 c.344+2dup Pathogenic ★ same condition
ABCB4 p.Ala294fs Pathogenic ★ same condition
ABCB4 p.Ile1034fs Pathogenic ★ same condition
ABCB4 p.Ile587fs Pathogenic ★ same condition
ABCB4 p.Ile735fs Pathogenic ★ same condition
ABCB4 p.Leu23fs Pathogenic ★ same condition
ABCB4 p.Ser1146fs 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-leu724fs (accessed [today's date]).

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