Is ABCC8 p.Arg1420Ser (c.4258C>A) pathogenic?

ABCC8 p.Arg1420Ser (c.4258C>A) is classified Likely pathogenic in ABCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-04). AlphaMissense: likely pathogenic (0.8264); Absent from gnomAD v4.1.

How common is ABCC8 p.Arg1420Ser (c.4258C>A) in the general population?

ABCC8 p.Arg1420Ser (c.4258C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ABCC8 p.Arg1420Ser (c.4258C>A)?

AlphaMissense predicts likely pathogenic (score 0.8264) — an in-silico prediction, not a clinical call.

ABCC8 p.Arg1420Ser

c.4258C>A · rs28938469 · VCV1464709

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8264 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,561,052)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8264	likely pathogenic ✓ concordant with ClinVar
REVEL	0.858	moderately pathogenic-leaning
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.22	acceptor loss, 21 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 8.7	GERP 0.18, 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

No allele count reported in gnomAD v4.1 (AN 1,561,052). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ABCC8
Protein: p.Arg1420Ser
Coding: c.4258C>A
MANE Select: NM_000352
dbSNP: rs28938469
Type: single nucleotide variant
Location: chr11:17395659 (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 1420: a UniProt-annotated variant site (in hhf1; modest impairment of channel function); an α-helix; the abc transporter 2 domain

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

Similar variants

ABCC8 p.Arg1420Cys Pathogenic/Likely pathogenic ★★ ⚠ same residue
ABCC8 p.Arg1420His Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC8 c.1176+2T>C Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.1333-1013A>G Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.148+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.148+2T>G Likely pathogenic ★★ same type
ABCC8 c.1630+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.1630+1G>T Pathogenic ★★ same type

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-arg1420ser (accessed [today's date]).

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