Is ABCC8 p.Pro207Leu (c.620C>T) pathogenic?

ABCC8 p.Pro207Leu (c.620C>T) is classified Uncertain significance in ABCC8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-14). AlphaMissense: likely pathogenic (0.9238); Very rare (popmax 0.00103%); Associated with maturity-onset diabetes of the young.

What condition is associated with ABCC8 p.Pro207Leu (c.620C>T)?

ABCC8 p.Pro207Leu (c.620C>T) is associated with maturity-onset diabetes of the young, type 2 diabetes mellitus, hypoglycemia, leucine-induced (ClinVar).

How common is ABCC8 p.Pro207Leu (c.620C>T) in the general population?

ABCC8 p.Pro207Leu (c.620C>T) is very rare (popmax 0.00103%) (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.Pro207Leu (c.620C>T)?

AlphaMissense predicts likely pathogenic (score 0.9238) — an in-silico prediction, not a clinical call.

ABCC8 p.Pro207Leu

c.620C>T · rs750165947 · VCV878388

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9238 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00103%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

maturity-onset diabetes of the young

Computational evidence

Protein change
AlphaMissense	0.9238	likely pathogenic
REVEL	0.621	indeterminate
SaProt	LLR -9.26	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	24.4	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 0.00103%

Overall 0.00103% 15/1,461,888 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
Remaining individualsnot grpmax-eligible	0.0048%	20,837

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro207Leu
Coding: c.620C>T
MANE Select: NM_000352
dbSNP: rs750165947
Type: single nucleotide variant
Location: chr11:17461785 (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 207: a UniProt-annotated variant site (in pndm3; likely pathogenic; reduced inhibition by atp)

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: type 2 diabetes mellitus hypoglycemia, leucine-induced hyperinsulinemic hypoglycemia, familial, 1 diabetes mellitus, transient neonatal, 2 transient neonatal diabetes mellitus diabetes mellitus, permanent neonatal 3 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.Pro207fs Pathogenic ★ same residue
ABCC8 p.Pro207= 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-pro207leu (accessed [today's date]).

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