Is KCNT1 p.Pro229= (c.687G>A) pathogenic?

KCNT1 p.Pro229= (c.687G>A) is classified Likely benign in KCNT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-01). Very rare (popmax 0.0011%, sas); Associated with developmental and epileptic encephalopathy, 14.

What condition is associated with KCNT1 p.Pro229= (c.687G>A)?

KCNT1 p.Pro229= (c.687G>A) is associated with developmental and epileptic encephalopathy, 14, autosomal dominant nocturnal frontal lobe epilepsy 5 (ClinVar).

How common is KCNT1 p.Pro229= (c.687G>A) in the general population?

KCNT1 p.Pro229= (c.687G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

KCNT1 p.Pro229=

c.687G>A · rs748796809 · VCV1141506

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

developmental and epileptic encephalopathy, 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.7	GERP -3.9
Overall
CADD	4.495	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,060 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000806% 13/1,612,192 alleles · very rare exomes 12/1,460,242 · genomes 1/151,950 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00801%	12,483
Remaining individualsnot grpmax-eligible	0.0032%	31,229
South Asiangrpmax	0.0011%	91,060
European (non-Finnish)	0.000424%	235,997

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro229=
Coding: c.687G>A
MANE Select: NM_020822
dbSNP: rs748796809
Type: single nucleotide variant
Location: chr9:135757309 (GRCh38)
Gene constraint: LOEUF 0.682 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.94 · 6 PDB
Residue 229: an α-helix

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

Disease context

developmental and epileptic encephalopathy, 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nocturnal frontal lobe epilepsy 5

Similar variants

KCNT1 p.Pro229Leu 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-pro229 (accessed [today's date]).

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