Is ABCC2 p.Val417Ala (c.1250T>C) pathogenic?

ABCC2 p.Val417Ala (c.1250T>C) is classified Conflicting classifications of pathogenicity in ABCC2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-01). AlphaMissense: likely benign (0.1539); Ultra-rare (popmax 0.0854%, nfe); Associated with Dubin-Johnson syndrome.

What condition is associated with ABCC2 p.Val417Ala (c.1250T>C)?

ABCC2 p.Val417Ala (c.1250T>C) is associated with Dubin-Johnson syndrome (ClinVar).

How common is ABCC2 p.Val417Ala (c.1250T>C) in the general population?

ABCC2 p.Val417Ala (c.1250T>C) is ultra-rare (popmax 0.0854%, 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.Val417Ala (c.1250T>C)?

AlphaMissense predicts likely benign (score 0.1539) — an in-silico prediction, not a clinical call.

ABCC2 p.Val417Ala

c.1250T>C · rs199595780 · VCV298450

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1539 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0854%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Dubin-Johnson syndrome

Computational evidence

Protein change
AlphaMissense	0.1539	likely benign
REVEL	0.339	indeterminate
SaProt	LLR -8.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 2.5, phastCons 0.94
Regional constraint	o/e 0.98	unconstrained · MANE · 69 kb · p 0.48 · regional, not allelic
Overall
CADD	18.32	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 0.0854% European (non-Finnish) · 1,008/1,180,020 alleles

Filtering AF 0.081% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0793%

Overall 0.0655% 1,057/1,614,014 alleles · ultra-rare exomes 1,005/1,461,864 · genomes 52/152,150 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0854%	1,171
Remaining individualsnot grpmax-eligible	0.0352%	2,840
Admixed American	0.0233%	4,286
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
African / African-American	0.00667%	14,982
South Asian	0.00549%	18,214

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.Val417Ala
Coding: c.1250T>C
MANE Select: NM_000392
dbSNP: rs199595780
Type: single nucleotide variant
Location: chr10:99804059 (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.Val417Ile Benign/Likely benign ★★ 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-val417ala (accessed [today's date]).

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