Is KCNT2 p.Pro676= (c.2028A>G) pathogenic?

KCNT2 p.Pro676= (c.2028A>G) is classified Likely benign in KCNT2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-09-10). Very rare (popmax 0.000427%, nfe); Associated with KCNT2-related disorder.

What condition is associated with KCNT2 p.Pro676= (c.2028A>G)?

KCNT2 p.Pro676= (c.2028A>G) is associated with KCNT2-related disorder (ClinVar).

How common is KCNT2 p.Pro676= (c.2028A>G) in the general population?

KCNT2 p.Pro676= (c.2028A>G) is very rare (popmax 0.000427%, nfe) (gnomAD).

KCNT2 p.Pro676=

c.2028A>G · VCV3355510

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000427%, nfe)

Conditions

KCNT2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1	GERP -3.8, phastCons 0.003
Overall
CADD	6.301	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000427% European (non-Finnish) · 5/1,171,270 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000312% 5/1,604,000 alleles · very rare exomes 4/1,451,980 · genomes 1/152,020 · joint denominator

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: KCNT2
Protein: p.Pro676=
Coding: c.2028A>G
MANE Select: NM_198503
Type: single nucleotide variant
Location: chr1:196331231 (GRCh38)
Gene constraint: LOEUF 0.744 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.42

Full KCNT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

KCNT2-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KCNT2 c.175+1G>T Likely pathogenic ★ same condition
KCNT2 p.Phe240Leu Pathogenic ★ ⚠ same condition
KCNT2 p.Arg1020Lys Uncertain significance ⚠ same condition
KCNT2 p.Arg740Lys Uncertain significance ⚠ same condition
KCNT2 p.Leu371Phe Uncertain significance ⚠ same condition
KCNT2 p.Asn40Lys Likely benign ⚠ same condition
KCNT2 p.Leu1084= Likely benign same condition
KCNT2 p.Ter1136= Likely benign 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/kcnt2-p-pro676 (accessed [today's date]).

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