Is KCNT1 p.Val593Met (c.1777G>A) pathogenic?

KCNT1 p.Val593Met (c.1777G>A) is classified Conflicting classifications of pathogenicity in KCNT1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-31). AlphaMissense: likely pathogenic (0.8688); Ultra-rare (popmax 0.0676%, amr); Associated with Inborn genetic diseases.

What condition is associated with KCNT1 p.Val593Met (c.1777G>A)?

KCNT1 p.Val593Met (c.1777G>A) is associated with Inborn genetic diseases, developmental and epileptic encephalopathy, 14, autosomal dominant nocturnal frontal lobe epilepsy 5 (ClinVar).

How common is KCNT1 p.Val593Met (c.1777G>A) in the general population?

KCNT1 p.Val593Met (c.1777G>A) is ultra-rare (popmax 0.0676%, amr) (gnomAD).

What do computational predictors say about KCNT1 p.Val593Met (c.1777G>A)?

AlphaMissense predicts likely pathogenic (score 0.8688) — an in-silico prediction, not a clinical call.

KCNT1 p.Val593Met

c.1777G>A · rs779590747 · VCV374766

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8688 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0676%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8688	likely pathogenic
REVEL	0.398	indeterminate
SaProt	LLR -14.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
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	27.6	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 V574M vs ClinVar V593M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0676% Admixed American · 36/53,286 alleles

Filtering AF 0.0502% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0441%

Overall 0.00382% 60/1,570,012 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0676%	1,480
African / African-American	0.00811%	12,330
Remaining individualsnot grpmax-eligible	0.00493%	20,269
European (non-Finnish)	0.00121%	82,616
South Asian	0.00116%	86,200

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.Val593Met
Coding: c.1777G>A
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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 14 autosomal dominant nocturnal frontal lobe epilepsy 5

Similar variants

KCNT1 p.Val593Leu Uncertain significance ★ ⚠ 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-val593met (accessed [today's date]).

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