Is ABCC2 p.Arg1174His (c.3521G>A) pathogenic?

ABCC2 p.Arg1174His (c.3521G>A) is classified Conflicting classifications of pathogenicity in ABCC2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-02). AlphaMissense: ambiguous (0.3736); Rare (popmax 0.15%, afr); Associated with Dubin-Johnson syndrome.

What condition is associated with ABCC2 p.Arg1174His (c.3521G>A)?

ABCC2 p.Arg1174His (c.3521G>A) is associated with Dubin-Johnson syndrome (ClinVar).

How common is ABCC2 p.Arg1174His (c.3521G>A) in the general population?

ABCC2 p.Arg1174His (c.3521G>A) is rare (popmax 0.15%, afr) (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.Arg1174His (c.3521G>A)?

AlphaMissense predicts ambiguous (score 0.3736) — an in-silico prediction, not a clinical call.

ABCC2 p.Arg1174His

c.3521G>A · rs139188247 · VCV500796

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3736 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.15%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Dubin-Johnson syndrome

Computational evidence

Protein change
AlphaMissense	0.3736	ambiguous
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -10.69	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 69 kb · p 0.48 · regional, not allelic
Overall
CADD	27.1	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 0.15% African / African-American · 112/74,916 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.119%

Overall 0.0111% 179/1,614,066 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.15%	669
Middle Eastern	0.0493%	2,027
Remaining individualsnot grpmax-eligible	0.0224%	4,463
Admixed American	0.0117%	8,571
East Asian	0.00445%	22,448
South Asian	0.00329%	30,362
European (non-Finnish)	0.00322%	31,054

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.Arg1174His
Coding: c.3521G>A
MANE Select: NM_000392
dbSNP: rs139188247
Type: single nucleotide variant
Location: chr10:99836197 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 16 PDB
Residue 1174: an α-helix; the abc transmembrane type-1 2 domain; a UniProt-annotated variant site (decreased expression; altered subcellular localization; decreased transporter activity)

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.Arg1174Cys Uncertain significance ★ ⚠ 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
ABCC2 c.576+1G>A 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-arg1174his (accessed [today's date]).

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