Is ABCC8 p.Arg1436Gln (c.4307G>A) pathogenic?

ABCC8 p.Arg1436Gln (c.4307G>A) is classified Pathogenic in ABCC8 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-12-31). AlphaMissense: likely pathogenic (0.6849); Very rare (popmax 0.00273%, afr); Associated with Hereditary hyperinsulinism.

What condition is associated with ABCC8 p.Arg1436Gln (c.4307G>A)?

ABCC8 p.Arg1436Gln (c.4307G>A) is associated with Hereditary hyperinsulinism, type 2 diabetes mellitus, hyperinsulinemic hypoglycemia, familial, 1 (ClinVar).

How common is ABCC8 p.Arg1436Gln (c.4307G>A) in the general population?

ABCC8 p.Arg1436Gln (c.4307G>A) is very rare (popmax 0.00273%, afr) (gnomAD).

What do computational predictors say about ABCC8 p.Arg1436Gln (c.4307G>A)?

AlphaMissense predicts likely pathogenic (score 0.6849) — an in-silico prediction, not a clinical call.

ABCC8 p.Arg1436Gln

c.4307G>A · rs387906407 · VCV9086

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.6849 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00273%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary hyperinsulinism

Computational evidence

Protein change
AlphaMissense	0.6849	likely pathogenic ✓ concordant with ClinVar
REVEL	0.976	strongly pathogenic-leaning
SaProt	LLR -12.04	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.36	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	37.0	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

Grpmax group 0.00273% African / African-American · 2/73,204 alleles

Filtering AF 0.000453% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000267%

Overall 0.000774% 12/1,550,058 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00273%	36,602
Remaining individualsnot grpmax-eligible	0.00166%	60,160
European (non-Finnish)	0.000784%	127,573

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.Arg1436Gln
Coding: c.4307G>A
MANE Select: NM_000352
dbSNP: rs387906407
Type: single nucleotide variant
Location: chr11:17395610 (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 1436: a UniProt-annotated variant site (in hhf1; cannot form a functional channel, due to protein instability or defective transport to the membrane); an α-helix; the abc transporter 2 domain

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

Disease context

Hereditary hyperinsulinism

Also linked: type 2 diabetes mellitus hyperinsulinemic hypoglycemia, familial, 1 familial hyperinsulinism

Similar variants

ABCC8 p.Arg1436Ter Pathogenic/Likely pathogenic ★★ 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
ABCC8 c.1817+1G>C 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-arg1436gln (accessed [today's date]).

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