Is KCNT1 p.Arg910Pro (c.2729G>C) pathogenic?

KCNT1 p.Arg910Pro (c.2729G>C) is classified Uncertain significance in KCNT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-05). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with autosomal dominant nocturnal frontal lobe epilepsy 5.

What condition is associated with KCNT1 p.Arg910Pro (c.2729G>C)?

KCNT1 p.Arg910Pro (c.2729G>C) is associated with autosomal dominant nocturnal frontal lobe epilepsy 5, developmental and epileptic encephalopathy, 14 (ClinVar).

How common is KCNT1 p.Arg910Pro (c.2729G>C) in the general population?

KCNT1 p.Arg910Pro (c.2729G>C) 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.

What do computational predictors say about KCNT1 p.Arg910Pro (c.2729G>C)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

KCNT1 p.Arg910Pro

c.2729G>C · VCV3758571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nocturnal frontal lobe epilepsy 5

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic · top 1% in KCNT1
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -15.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.44	donor loss · deltas
Pangolin	Δ0.51	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.5	GERP 2, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 9,528 bp · p 5e-14 · regional, not allelic
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 R891P vs ClinVar R910P) — verify the residue.

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.Arg910Pro
Coding: c.2729G>C
MANE Select: NM_020822
Type: single nucleotide variant
Location: chr9:135778822 (GRCh38)
Gene constraint: LOEUF 0.682 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.94 · 6 PDB
Residue 891 UniProt numbering: an α-helix; the rck n-terminal 2 domain

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.Arg910Trp Uncertain significance ★★ ⚠ same residue
KCNT1 p.Arg910Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
KCNT1 p.Arg910Leu 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

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-arg910pro (accessed [today's date]).

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