Is ABCC2 p.Trp1003Leu (c.3008G>T) pathogenic?

ABCC2 p.Trp1003Leu (c.3008G>T) is classified Uncertain significance in ABCC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.911); Ultra-rare (popmax 0.0483%, nfe); Associated with Dubin-Johnson syndrome.

What condition is associated with ABCC2 p.Trp1003Leu (c.3008G>T)?

ABCC2 p.Trp1003Leu (c.3008G>T) is associated with Dubin-Johnson syndrome (ClinVar).

How common is ABCC2 p.Trp1003Leu (c.3008G>T) in the general population?

ABCC2 p.Trp1003Leu (c.3008G>T) is ultra-rare (popmax 0.0483%, nfe) (gnomAD).

How is Dubin-Johnson syndrome inherited?

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

What do computational predictors say about ABCC2 p.Trp1003Leu (c.3008G>T)?

AlphaMissense predicts likely pathogenic (score 0.911) — an in-silico prediction, not a clinical call.

ABCC2 p.Trp1003Leu

c.3008G>T · rs147566977 · VCV500765

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.911 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Dubin-Johnson syndrome

Computational evidence

Protein change
AlphaMissense	0.911	likely pathogenic
REVEL	0.894	moderately pathogenic-leaning
SaProt	LLR -9.85	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 69 kb · p 0.48 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0483% European (non-Finnish) · 570/1,180,018 alleles

Filtering AF 0.045% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0437%

Overall 0.0402% 649/1,614,156 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0672%	1,488
European (non-Finnish)grpmax	0.0483%	2,070
Admixed American	0.0417%	2,401
Middle Eastern	0.0165%	6,060
African / African-American	0.0147%	6,822

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: ABCC2
Protein: p.Trp1003Leu
Coding: c.3008G>T
MANE Select: NM_000392
dbSNP: rs147566977
Type: single nucleotide variant
Location: chr10:99831735 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 16 PDB
Residue 1003: 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.Trp1003Cys Uncertain significance ★★ ⚠ same residue
ABCC2 p.Trp1003Ter Pathogenic ★ same residue
ABCC2 c.1031+4A>G Pathogenic/Likely pathogenic ★★ same condition
ABCC2 c.3258+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC2 c.333+1G>A Likely pathogenic ★★ same condition
ABCC2 c.3415-1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC2 c.3741+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC2 c.3741+1G>T Pathogenic/Likely 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/abcc2-p-trp1003leu (accessed [today's date]).

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