Is ABCC2 p.Thr1251fs (c.3751dup) pathogenic?

ABCC2 p.Thr1251fs (c.3751dup) is classified Likely pathogenic in ABCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-13). Very rare (popmax 0.00017%, nfe); Associated with Dubin-Johnson syndrome.

What condition is associated with ABCC2 p.Thr1251fs (c.3751dup)?

ABCC2 p.Thr1251fs (c.3751dup) is associated with Dubin-Johnson syndrome (ClinVar).

How common is ABCC2 p.Thr1251fs (c.3751dup) in the general population?

ABCC2 p.Thr1251fs (c.3751dup) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Dubin-Johnson syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ABCC2 p.Thr1251fs

c.3751dup · VCV3589878

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Dubin-Johnson syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 27 of 32
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,836 alleles

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

Overall 0.000137% 2/1,461,638 alleles · very 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: ABCC2
Protein: p.Thr1251fs
Coding: c.3751dup
MANE Select: NM_000392
Type: Duplication
Location: chr10:99843805 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 16 PDB
Residue 1251: an α-helix; the abc transmembrane type-1 2 domain

Full ABCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Dubin-Johnson syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dubin-Johnson syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult

Similar variants

ABCC2 p.Asp1073Ter Pathogenic ★★ same condition
ABCC2 p.Leu1213fs Pathogenic ★★ same condition
ABCC2 p.Lys298fs Pathogenic ★★ same condition
ABCC2 p.Val667fs Pathogenic/Likely pathogenic ★★ same condition
ABCC2 p.Asp304fs Likely pathogenic ★ same condition
ABCC2 p.Tyr119fs Pathogenic ★ same condition
ABCC2 p.Tyr1309fs Likely pathogenic ★ same condition
ABCC2 p.Thr1251Ile Uncertain significance ★ ⚠ same residue

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/abcc2-p-thr1251fs (accessed [today's date]).

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