Is ABCC2 p.His1414Tyr (c.4240C>T) pathogenic?

ABCC2 p.His1414Tyr (c.4240C>T) is classified Uncertain significance in ABCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-05). AlphaMissense: likely benign (0.2576); Ultra-rare (popmax 0.0891%, eas).

How common is ABCC2 p.His1414Tyr (c.4240C>T) in the general population?

ABCC2 p.His1414Tyr (c.4240C>T) is ultra-rare (popmax 0.0891%, eas) (gnomAD).

What do computational predictors say about ABCC2 p.His1414Tyr (c.4240C>T)?

AlphaMissense predicts likely benign (score 0.2576) — an in-silico prediction, not a clinical call.

ABCC2 p.His1414Tyr

c.4240C>T · rs544311254 · VCV597911

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2576 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0891%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2576	likely benign
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -10.57	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 69 kb · p 0.48 · regional, not allelic
Overall
CADD	26.9	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 0.0891% East Asian · 40/44,884 alleles

Filtering AF 0.0673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0596%

Overall 0.00266% 43/1,614,218 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0891%	1,122
Remaining individualsnot grpmax-eligible	0.0016%	62,512
African / African-American	0.00133%	75,058
South Asian	0.0011%	91,080

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.His1414Tyr
Coding: c.4240C>T
MANE Select: NM_000392
dbSNP: rs544311254
Type: single nucleotide variant
Location: chr10:99847054 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 16 PDB
Residue 1414: the abc transporter 2 domain

Full ABCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCC2 p.His1414= Likely benign ★ same residue
ABCC2 p.His1414fs Pathogenic ★ same residue
ABCC2 c.1031+4A>G Pathogenic/Likely pathogenic ★★ same type
ABCC2 c.1967+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCC2 c.1968-1G>C Pathogenic/Likely pathogenic ★★ same type
ABCC2 c.3258+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCC2 c.333+1G>A Likely pathogenic ★★ same type
ABCC2 c.3414+1G>A Likely pathogenic ★★ same type

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-his1414tyr (accessed [today's date]).

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