Is ABCC2 p.Ile1173Phe (c.3517A>T) pathogenic?

ABCC2 p.Ile1173Phe (c.3517A>T) is classified Pathogenic in ABCC2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-04-17). AlphaMissense: likely pathogenic (0.8835); Rare (popmax 0.23%, mid); Associated with Dubin-Johnson syndrome.

What condition is associated with ABCC2 p.Ile1173Phe (c.3517A>T)?

ABCC2 p.Ile1173Phe (c.3517A>T) is associated with Dubin-Johnson syndrome (ClinVar).

How common is ABCC2 p.Ile1173Phe (c.3517A>T) in the general population?

ABCC2 p.Ile1173Phe (c.3517A>T) is rare (popmax 0.23%, mid) (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.Ile1173Phe (c.3517A>T)?

AlphaMissense predicts likely pathogenic (score 0.8835) — an in-silico prediction, not a clinical call.

ABCC2 p.Ile1173Phe

c.3517A>T · rs72558201 · VCV8418

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8835 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.23%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Dubin-Johnson syndrome

Computational evidence

Protein change
AlphaMissense	0.8835	likely pathogenic ✓ concordant with ClinVar
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -13.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 69 kb · p 0.48 · regional, not allelic
Overall
CADD	24.9	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 0.23% Middle Eastern · 14/6,084 alleles

Filtering AF 0.139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.111%

Overall 0.0013% 21/1,614,090 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.23%	435
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00133%	74,928
European (non-Finnish)	0.000254%	393,351

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.Ile1173Phe
Coding: c.3517A>T
MANE Select: NM_000392
dbSNP: rs72558201
Type: single nucleotide variant
Location: chr10:99836193 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 16 PDB
Residue 1173: an α-helix; the abc transmembrane type-1 2 domain; a UniProt-annotated variant site (in djs; decreased expression and mislocation to the endoplasmic reticulum)

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 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
ABCC2 c.576+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC2 p.Arg1066Ter 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-ile1173phe (accessed [today's date]).

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