Is ABCB4 p.Ser339fs (c.1015del) pathogenic?

ABCB4 p.Ser339fs (c.1015del) is classified Pathogenic/Likely pathogenic in ABCB4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-04-14). Very rare (popmax 0.00172%, amr); Associated with ABCB4-related disorder.

What condition is associated with ABCB4 p.Ser339fs (c.1015del)?

ABCB4 p.Ser339fs (c.1015del) is associated with ABCB4-related disorder, gallbladder disease 1, cholestasis, intrahepatic, of pregnancy, 3 (ClinVar).

How common is ABCB4 p.Ser339fs (c.1015del) in the general population?

ABCB4 p.Ser339fs (c.1015del) is very rare (popmax 0.00172%, amr) (gnomAD).

ABCB4 p.Ser339fs

c.1015del · rs753104429 · VCV500242

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00172%, amr)

Conditions

ABCB4-related disorder

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 10 of 28
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.7	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 0.00172% Admixed American · 1/58,026 alleles

Filtering AF 0.000508% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000372%

Overall 0.00114% 18/1,573,422 alleles · very rare exomes 18/1,424,040 · genomes 0/149,382 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00771%	12,967
Ashkenazi Jewishnot grpmax-eligible	0.00347%	28,806
Admixed Americangrpmax	0.00172%	58,026
South Asian	0.00113%	88,540
European (non-Finnish)	0.000947%	105,559

Finnish 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.Ser339fs
Coding: c.1015del
MANE Select: NM_000443
dbSNP: rs753104429
Type: Deletion
Location: chr7:87444966 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 339: an α-helix; the abc transmembrane type-1 1 domain

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

Disease context

ABCB4-related disorder

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

Similar variants

ABCB4 p.Asp682fs Pathogenic ★★ same condition
ABCB4 p.Gln458fs Pathogenic ★★ same condition
ABCB4 p.Leu518fs Pathogenic/Likely pathogenic ★★ same condition
ABCB4 p.Lys1026fs Pathogenic/Likely pathogenic ★★ same condition
ABCB4 p.Lys30fs Pathogenic/Likely pathogenic ★★ same condition
ABCB4 p.Thr34fs Pathogenic/Likely pathogenic ★★ same condition
ABCB4 p.Cys433_Gly434del Uncertain significance ★★ same condition
ABCB4 c.1231-81del Benign ★★ 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-ser339fs (accessed [today's date]).

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