Is KCNT2 p.Pro745Ser (c.2233C>T) pathogenic?

KCNT2 p.Pro745Ser (c.2233C>T) is classified Uncertain significance in KCNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.2619); Very rare (popmax 0.00469%, eas); Associated with Inborn genetic diseases.

What condition is associated with KCNT2 p.Pro745Ser (c.2233C>T)?

KCNT2 p.Pro745Ser (c.2233C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KCNT2 p.Pro745Ser (c.2233C>T) in the general population?

KCNT2 p.Pro745Ser (c.2233C>T) is very rare (popmax 0.00469%, eas) (gnomAD).

What do computational predictors say about KCNT2 p.Pro745Ser (c.2233C>T)?

AlphaMissense predicts likely benign (score 0.2619) — an in-silico prediction, not a clinical call.

KCNT2 p.Pro745Ser

c.2233C>T · rs752227943 · VCV3113511

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00469%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2619	likely benign
REVEL	0.403	indeterminate
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 5, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 57 kb · p 0.0014 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00469% East Asian · 2/42,636 alleles

Filtering AF 0.000777% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000291%

Overall 0.000192% 3/1,564,968 alleles · very rare exomes 3/1,412,862 · genomes 0/152,106 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00469%	21,318
European (non-Finnish)	8.61e-05%	1,161,626

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: KCNT2
Protein: p.Pro745Ser
Coding: c.2233C>T
MANE Select: NM_198503
dbSNP: rs752227943
Type: single nucleotide variant
Location: chr1:196326760 (GRCh38)
Gene constraint: LOEUF 0.744 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.42
Residue 745: the rck n-terminal 2 domain

Full KCNT2 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

Similar variants

KCNT2 p.Pro745Gln Uncertain significance ★ same residue
KCNT2 p.Ala609Val Uncertain significance ★★ ⚠ same condition
KCNT2 p.Cys484Phe Uncertain significance ★★ ⚠ same condition
KCNT2 p.Leu116Val Uncertain significance ★★ ⚠ same condition
KCNT2 p.Leu536Pro Uncertain significance ★★ ⚠ same condition
KCNT2 p.Met807Val Uncertain significance ★★ ⚠ same condition
KCNT2 p.Met892Val Uncertain significance ★★ ⚠ same condition
KCNT2 p.Ser1029Ala Uncertain significance ★★ ⚠ 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/kcnt2-p-pro745ser (accessed [today's date]).

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