Is ABCC2 p.Val417Ile (c.1249G>A) pathogenic?

ABCC2 p.Val417Ile (c.1249G>A) is classified Benign/Likely benign in ABCC2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-28). AlphaMissense: likely benign (0.0681); Common (popmax 27.7%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Dubin-Johnson syndrome.

What condition is associated with ABCC2 p.Val417Ile (c.1249G>A)?

ABCC2 p.Val417Ile (c.1249G>A) is associated with Dubin-Johnson syndrome (ClinVar).

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.Val417Ile (c.1249G>A)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

ABCC2 p.Val417Ile

Q: How common is ABCC2 p.Val417Ile (c.1249G>A) in the general population?

ABCC2 p.Val417Ile (c.1249G>A) is common (popmax 27.7%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1249G>A · rs2273697 · VCV255992

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 27.7%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Dubin-Johnson syndrome

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -8.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.9	GERP -5.1
Regional constraint	o/e 0.98	unconstrained · MANE · 69 kb · p 0.48 · regional, not allelic
Overall
CADD	0.023	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 27.7% South Asian · 25,183/91,070 alleles

Filtering AF 27.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 27.2%

Overall 19.9% 320,871/1,613,940 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	27.7%	4
Middle Eastern	26.1%	4
Ashkenazi Jewishnot grpmax-eligible	21.3%	5
European (non-Finnish)	20.1%	5
Remaining individualsnot grpmax-eligible	18.8%	5
African / African-American	18.4%	5
Finnishnot grpmax-eligible	16.5%	6
Admixed American	15.4%	6
Amishnot grpmax-eligible	12.2%	8
East Asian	10.6%	9

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.Val417Ile
Coding: c.1249G>A
MANE Select: NM_000392
dbSNP: rs2273697
Type: single nucleotide variant
Location: chr10:99804058 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 16 PDB
Residue 417: an α-helix; the abc transmembrane type-1 1 domain; a UniProt-annotated variant site (in)

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.Val417Ala Conflicting classifications of pathogenicity ★ ⚠ 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-val417ile (accessed [today's date]).

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