Is ABCC8 p.Ala1369Ser (c.4105G>T) pathogenic?

ABCC8 p.Ala1369Ser (c.4105G>T) is classified Benign in ABCC8 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0597); Common (popmax 93.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with diabetes mellitus, permanent neonatal 3.

What condition is associated with ABCC8 p.Ala1369Ser (c.4105G>T)?

ABCC8 p.Ala1369Ser (c.4105G>T) is associated with diabetes mellitus, permanent neonatal 3, type 2 diabetes mellitus, hypoglycemia, leucine-induced (ClinVar).

How is Isolated permanent neonatal diabetes mellitus inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCC8 p.Ala1369Ser (c.4105G>T)?

AlphaMissense predicts likely benign (score 0.0597) — an in-silico prediction, not a clinical call.

ABCC8 p.Ala1369Ser

Q: How common is ABCC8 p.Ala1369Ser (c.4105G>T) in the general population?

ABCC8 p.Ala1369Ser (c.4105G>T) is common (popmax 93.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4105G>T · rs757110 · VCV157699

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0597 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 93.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

diabetes mellitus, permanent neonatal 3

Computational evidence

Protein change
AlphaMissense	0.0597	likely benign
REVEL	0.513	indeterminate
SaProt	LLR -5.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -5.5, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	2.386	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 93.9% African / African-American · 70,456/75,002 alleles

Filtering AF 93.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 93.1%

Overall 64.7% 1,043,430/1,613,778 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	93.9%	1
Middle Eastern	71.2%	1
Remaining individualsnot grpmax-eligible	65.2%	2
European (non-Finnish)	63.9%	2
Admixed American	63.6%	2
South Asian	61.7%	2
Ashkenazi Jewishnot grpmax-eligible	61.7%	2
East Asian	61.6%	2
Finnishnot grpmax-eligible	52.3%	2
Amishnot grpmax-eligible	48%	2

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: ABCC8
Protein: p.Ala1369Ser
Coding: c.4105G>T
MANE Select: NM_000352
dbSNP: rs757110
Type: single nucleotide variant
Location: chr11:17396930 (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 1369: a UniProt-annotated variant site (in); the abc transporter 2 domain

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

Disease context

diabetes mellitus, permanent neonatal 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: type 2 diabetes mellitus hypoglycemia, leucine-induced hyperinsulinemic hypoglycemia, familial, 1 diabetes mellitus, transient neonatal, 2

For Isolated permanent neonatal diabetes mellitus (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ABCC8 p.Ala1369Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC8 p.Ala1369= Likely benign ★ same residue
ABCC8 c.1176+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.1333-1013A>G Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.148+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.148+2T>G Likely pathogenic ★★ same condition
ABCC8 c.1630+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.1630+1G>T 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-ala1369ser (accessed [today's date]).

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