Is ABCC8 p.Ser1422Cys (c.4265C>G) pathogenic?

ABCC8 p.Ser1422Cys (c.4265C>G) is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2017-04-05). AlphaMissense: ambiguous (0.5472); Absent from gnomAD v4.1; Associated with maturity-onset diabetes of the young.

What condition is associated with ABCC8 p.Ser1422Cys (c.4265C>G)?

ABCC8 p.Ser1422Cys (c.4265C>G) is associated with maturity-onset diabetes of the young, transient neonatal diabetes mellitus, permanent neonatal diabetes mellitus (ClinVar).

How common is ABCC8 p.Ser1422Cys (c.4265C>G) in the general population?

ABCC8 p.Ser1422Cys (c.4265C>G) is absent from gnomAD v4.1 (gnomAD).

How is MODY inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCC8 p.Ser1422Cys (c.4265C>G)?

AlphaMissense predicts ambiguous (score 0.5472) — an in-silico prediction, not a clinical call.

ABCC8 p.Ser1422Cys

c.4265C>G · rs1554904936 · VCV434057

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5472 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

maturity-onset diabetes of the young

Computational evidence

Protein change
AlphaMissense	0.5472	ambiguous
REVEL	0.907	moderately pathogenic-leaning
SaProt	LLR -8.40	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	32.0	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

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.Ser1422Cys
Coding: c.4265C>G
MANE Select: NM_000352
dbSNP: rs1554904936
Type: single nucleotide variant
Location: chr11:17395652 (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 1422: a β-strand; the abc transporter 2 domain

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

Disease context

maturity-onset diabetes of the young — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: transient neonatal diabetes mellitus permanent neonatal diabetes mellitus

For MODY (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ABCC8 p.Ser1422Thr Likely pathogenic ★ ⚠ same residue
ABCC8 c.2116+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.3868-1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.3989-9G>A Pathogenic ★★ same condition
ABCC8 c.4308-2A>G Pathogenic/Likely pathogenic ★★ same condition
ABCC8 p.Arg1182Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCC8 p.Arg1379Cys Pathogenic/Likely pathogenic ★★ same condition
ABCC8 p.Arg1379His 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/abcc8-p-ser1422cys (accessed [today's date]).

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