Is KCNT1 p.Val593Leu (c.1777G>C) pathogenic?

KCNT1 p.Val593Leu (c.1777G>C) is classified Uncertain significance in KCNT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-22). AlphaMissense: likely pathogenic (0.8849); Very rare (popmax 8.65e-05%, nfe); Associated with autosomal dominant nocturnal frontal lobe epilepsy 5.

What condition is associated with KCNT1 p.Val593Leu (c.1777G>C)?

KCNT1 p.Val593Leu (c.1777G>C) is associated with autosomal dominant nocturnal frontal lobe epilepsy 5, developmental and epileptic encephalopathy, 14 (ClinVar).

How common is KCNT1 p.Val593Leu (c.1777G>C) in the general population?

KCNT1 p.Val593Leu (c.1777G>C) is very rare (popmax 8.65e-05%, 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.Val593Leu (c.1777G>C)?

AlphaMissense predicts likely pathogenic (score 0.8849) — an in-silico prediction, not a clinical call.

KCNT1 p.Val593Leu

c.1777G>C · rs779590747 · VCV2935049

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8849 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.65e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nocturnal frontal lobe epilepsy 5

Computational evidence

Protein change
AlphaMissense	0.8849	likely pathogenic
REVEL	0.281	benign-leaning
SaProt	LLR -12.56	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,978 bp · p 0.61 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V574L vs ClinVar V593L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.65e-05% European (non-Finnish) · 1/1,156,626 alleles

Overall 0.000657% 1/152,170 alleles · very rare

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.Val593Leu
Coding: c.1777G>C
MANE Select: NM_020822
dbSNP: rs779590747
Type: single nucleotide variant
Location: chr9:135770864 (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.Val593Met Conflicting classifications of pathogenicity ★ ⚠ same residue
KCNT1 p.Val593= Likely benign ★ 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-val593leu (accessed [today's date]).

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