Is KCNT1 p.Cys1069Ser (c.3205T>A) pathogenic?

KCNT1 p.Cys1069Ser (c.3205T>A) is classified Uncertain significance in KCNT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-20). AlphaMissense: likely benign (0.0946); Very rare (popmax 0.000254%, nfe); Associated with autosomal dominant nocturnal frontal lobe epilepsy 5.

How common is KCNT1 p.Cys1069Ser (c.3205T>A) in the general population?

KCNT1 p.Cys1069Ser (c.3205T>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

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

What do computational predictors say about KCNT1 p.Cys1069Ser (c.3205T>A)?

AlphaMissense predicts likely benign (score 0.0946) — an in-silico prediction, not a clinical call.

KCNT1 p.Cys1069Ser

Q: What condition is associated with KCNT1 p.Cys1069Ser (c.3205T>A)?

KCNT1 p.Cys1069Ser (c.3205T>A) is associated with autosomal dominant nocturnal frontal lobe epilepsy 5, developmental and epileptic encephalopathy, 14 (ClinVar).

c.3205T>A · rs781225639 · VCV656481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nocturnal frontal lobe epilepsy 5

Computational evidence

Protein change
AlphaMissense	0.0946	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -3.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP -1.1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,316 bp · p 0.49 · regional, not allelic
Overall
CADD	14.57	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C1043S vs ClinVar C1069S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,230 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,610,952 alleles · very rare exomes 3/1,459,064 · genomes 0/151,888 · 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: KCNT1
Protein: p.Cys1069Ser
Coding: c.3205T>A
MANE Select: NM_020822
dbSNP: rs781225639
Type: single nucleotide variant
Location: chr9:135786224 (GRCh38)
Gene constraint: LOEUF 0.682 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.94 · 6 PDB

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.Cys1069Tyr 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
KCNT1 p.Arg398Gln 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-cys1069ser (accessed [today's date]).

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