Is ABCB4 p.Cys1124fs (c.3370dup) pathogenic?

ABCB4 p.Cys1124fs (c.3370dup) is classified Pathogenic/Likely pathogenic in ABCB4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-12). Ultra-rare (popmax 0.04%, amr).

How common is ABCB4 p.Cys1124fs (c.3370dup) in the general population?

ABCB4 p.Cys1124fs (c.3370dup) is ultra-rare (popmax 0.04%, amr) (gnomAD).

ABCB4 p.Cys1124fs

c.3370dup · rs1315110517 · VCV2150294

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

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 26 of 28
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.033	GERP 1, phastCons 0.68
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% Admixed American · 24/60,000 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00149% 24/1,613,958 alleles · ultra-rare

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.Cys1124fs
Coding: c.3370dup
MANE Select: NM_000443
dbSNP: rs1315110517
Type: Duplication
Location: chr7:87406403 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 1124: the abc transporter 2 domain; a binding site

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

Similar variants

ABCB4 p.Cys1124Tyr Uncertain significance ★★ ⚠ same residue
ABCB4 p.Cys1124= Conflicting classifications of pathogenicity ★ same residue
ABCB4 p.Cys1124Arg Uncertain significance ★ ⚠ same residue
ABCB4 p.Ala204fs Pathogenic ★★ same type
ABCB4 p.Ile1242fs Pathogenic/Likely pathogenic ★★ same type
ABCB4 c.3486+10dup Benign/Likely benign ★★ same type
ABCB4 c.344+2dup Pathogenic ★ same type
ABCB4 p.Ala294fs Pathogenic ★ same type

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-cys1124fs (accessed [today's date]).

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