Is ABCC2 p.Met440Arg (c.1319T>G) pathogenic?

ABCC2 p.Met440Arg (c.1319T>G) is classified Uncertain significance in ABCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-09-29). AlphaMissense: ambiguous (0.4258); Very rare (popmax 0.00667%, afr).

How common is ABCC2 p.Met440Arg (c.1319T>G) in the general population?

ABCC2 p.Met440Arg (c.1319T>G) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about ABCC2 p.Met440Arg (c.1319T>G)?

AlphaMissense predicts ambiguous (score 0.4258) — an in-silico prediction, not a clinical call.

ABCC2 p.Met440Arg

c.1319T>G · rs996397410 · VCV594296

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Computational evidence

Protein change
AlphaMissense	0.4258	ambiguous
REVEL	0.389	indeterminate
SaProt	LLR -12.38	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.17, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 69 kb · p 0.48 · regional, not allelic
Overall
CADD	18.82	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 0.00667% African / African-American · 5/74,932 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000372% 6/1,614,078 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,986
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Met440Arg
Coding: c.1319T>G
MANE Select: NM_000392
dbSNP: rs996397410
Type: single nucleotide variant
Location: chr10:99804128 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.40 · 16 PDB
Residue 440: an α-helix; the abc transmembrane type-1 1 domain

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

Similar variants

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
ABCC2 c.3415-1G>A Pathogenic/Likely pathogenic ★★ same type
ABCC2 c.3741+1G>A Pathogenic/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-met440arg (accessed [today's date]).

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