Is ABCC8 c.3753+2C>T pathogenic?

ABCC8 c.3753+2C>T is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-06-05). Very rare (popmax 0.00133%, afr); Associated with Hereditary hyperinsulinism.

What condition is associated with ABCC8 c.3753+2C>T?

ABCC8 c.3753+2C>T is associated with Hereditary hyperinsulinism, familial hyperinsulinism, maturity-onset diabetes of the young (ClinVar).

How common is ABCC8 c.3753+2C>T in the general population?

ABCC8 c.3753+2C>T is very rare (popmax 0.00133%, afr) (gnomAD).

ABCC8 c.3753+2C>T

rs760196276 · VCV654797

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Hereditary hyperinsulinism

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.98 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.1	GERP -1.9, phastCons 1
Non-coding constraint	Z 2.92	1 kb window · o/e 0.80 · regional · uncalibrated
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,048 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000616% 9/1,461,792 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,048
European (non-Finnish)	0.000678%	147,497

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
Coding: c.3753+2C>T
MANE Select: NM_000352
dbSNP: rs760196276
Type: single nucleotide variant
Location: chr11:17398337 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.56 · 8 PDB

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

Disease context

Hereditary hyperinsulinism

Also linked: familial hyperinsulinism maturity-onset diabetes of the young transient neonatal diabetes mellitus

Similar variants

ABCC8 c.1176+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.1333-1013A>G Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.1630+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.2116+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.2117-1G>A Pathogenic ★★ same condition
ABCC8 c.2117-2A>T Pathogenic ★★ same condition
ABCC8 c.2222+1G>T Pathogenic ★★ same condition
ABCC8 c.2475+2T>A 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-c-3753-plus-2c-t (accessed [today's date]).

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