Is ABCC8 p.Ile1409Phe (c.4225A>T) pathogenic?

ABCC8 p.Ile1409Phe (c.4225A>T) is classified Uncertain significance in ABCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-17). AlphaMissense: likely pathogenic (0.8161); Absent from gnomAD v4.1.

How common is ABCC8 p.Ile1409Phe (c.4225A>T) in the general population?

ABCC8 p.Ile1409Phe (c.4225A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ABCC8 p.Ile1409Phe (c.4225A>T)?

AlphaMissense predicts likely pathogenic (score 0.8161) — an in-silico prediction, not a clinical call.

ABCC8 p.Ile1409Phe

c.4225A>T · VCV3339468

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8161 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8161	likely pathogenic
REVEL	0.991	strongly pathogenic-leaning
SaProt	LLR -12.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCC8
Protein: p.Ile1409Phe
Coding: c.4225A>T
MANE Select: NM_000352
Type: single nucleotide variant
Location: chr11:17395692 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.56 · 8 PDB
Residue 1409: a β-strand; the abc transporter 2 domain

Full ABCC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCC8 p.Ile1409= Conflicting classifications of pathogenicity ★ same residue
ABCC8 p.Ile1409Asn Uncertain significance ★ ⚠ same residue
ABCC8 p.Ile1409Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC8 c.1176+2T>C Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.1333-1013A>G Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.148+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.148+2T>G Likely pathogenic ★★ same type
ABCC8 c.1630+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/abcc8-p-ile1409phe (accessed [today's date]).

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