Is KCNT2 p.Pro422Ser (c.1264C>T) pathogenic?

KCNT2 p.Pro422Ser (c.1264C>T) is classified Uncertain significance in KCNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-01). AlphaMissense: likely pathogenic (0.9282); Absent from gnomAD v4.1.

How common is KCNT2 p.Pro422Ser (c.1264C>T) in the general population?

KCNT2 p.Pro422Ser (c.1264C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KCNT2 p.Pro422Ser (c.1264C>T)?

AlphaMissense predicts likely pathogenic (score 0.9282) — an in-silico prediction, not a clinical call.

KCNT2 p.Pro422Ser

c.1264C>T · rs1328309959 · VCV1691136

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9282 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9282	likely pathogenic
REVEL	0.527	indeterminate
SaProt	LLR -10.78	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 92 kb · p 2e-10 · regional, not allelic
Overall
CADD	27.5	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.

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: KCNT2
Protein: p.Pro422Ser
Coding: c.1264C>T
MANE Select: NM_198503
dbSNP: rs1328309959
Type: single nucleotide variant
Location: chr1:196398593 (GRCh38)
Gene constraint: LOEUF 0.744 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.42
Residue 422: the rck n-terminal 1 domain

Full KCNT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KCNT2 p.Ala609Val Uncertain significance ★★ ⚠ same type
KCNT2 p.Ala711Val Uncertain significance ★★ ⚠ same type
KCNT2 p.Arg879Gln Uncertain significance ★★ ⚠ same type
KCNT2 p.Asn29Lys Uncertain significance ★★ ⚠ same type
KCNT2 p.Cys484Phe Uncertain significance ★★ ⚠ same type
KCNT2 p.Leu116Val Uncertain significance ★★ ⚠ same type
KCNT2 p.Leu536Pro Uncertain significance ★★ ⚠ same type
KCNT2 p.Met807Val Uncertain significance ★★ ⚠ same type

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/kcnt2-p-pro422ser (accessed [today's date]).

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