Is KCNT1 p.Pro2Ser (c.4C>T) pathogenic?

KCNT1 p.Pro2Ser (c.4C>T) is classified Uncertain significance in KCNT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). Absent from gnomAD v4.1; Associated with autosomal dominant nocturnal frontal lobe epilepsy 5.

What condition is associated with KCNT1 p.Pro2Ser (c.4C>T)?

KCNT1 p.Pro2Ser (c.4C>T) is associated with autosomal dominant nocturnal frontal lobe epilepsy 5, developmental and epileptic encephalopathy, 14 (ClinVar).

How common is KCNT1 p.Pro2Ser (c.4C>T) in the general population?

KCNT1 p.Pro2Ser (c.4C>T) is absent from gnomAD v4.1 (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

KCNT1 p.Pro2Ser

c.4C>T · rs748898708 · VCV964279

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

autosomal dominant nocturnal frontal lobe epilepsy 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.03	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.35	GERP -0.3, phastCons 0.065
Regional constraint	o/e 1.16	unconstrained · MANE · 48 kb · p 0.042 · regional, not allelic
Overall
CADD	17.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: KCNT1
Protein: p.Pro2Ser
Coding: c.4C>T
MANE Select: NM_020822
dbSNP: rs748898708
Type: single nucleotide variant
Location: chr9:135702262 (GRCh38)
Gene constraint: LOEUF 0.682 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.94 · 6 PDB
Residue 2: the 'disordered' region

Full KCNT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant nocturnal frontal lobe epilepsy 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 14

For Sleep-related hypermotor epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

KCNT1 p.Pro2Ala Conflicting classifications of pathogenicity ★ same residue
KCNT1 p.Pro2Leu Uncertain significance ★ same residue
KCNT1 p.Ala477Thr Pathogenic/Likely pathogenic ★★ same condition
KCNT1 p.Ala934Ser Pathogenic/Likely pathogenic ★★ same condition
KCNT1 p.Ala934Thr Pathogenic ★★ same condition
KCNT1 p.Ala966Thr Pathogenic/Likely pathogenic ★★ same condition
KCNT1 p.Arg262Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
KCNT1 p.Arg356Trp Pathogenic/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/kcnt1-p-pro2ser (accessed [today's date]).

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