Is KCNT2 p.Asp377Glu (c.1131C>A) pathogenic?

KCNT2 p.Asp377Glu (c.1131C>A) is classified Uncertain significance in KCNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.289); Very rare (popmax 0.000342%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KCNT2 p.Asp377Glu (c.1131C>A)?

KCNT2 p.Asp377Glu (c.1131C>A) is associated with Inborn genetic diseases (ClinVar).

How common is KCNT2 p.Asp377Glu (c.1131C>A) in the general population?

KCNT2 p.Asp377Glu (c.1131C>A) is very rare (popmax 0.000342%, nfe) (gnomAD).

What do computational predictors say about KCNT2 p.Asp377Glu (c.1131C>A)?

AlphaMissense predicts likely benign (score 0.289) — an in-silico prediction, not a clinical call.

KCNT2 p.Asp377Glu

c.1131C>A · VCV4622592

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.289 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000342%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.289	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -9.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.41	GERP -3.5
Regional constraint	o/e 0.64	unconstrained · MANE · 92 kb · p 2e-10 · regional, not allelic
Overall
CADD	16.05	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 0.000342% European (non-Finnish) · 4/1,169,630 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000276% 4/1,446,734 alleles · very rare

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.Asp377Glu
Coding: c.1131C>A
MANE Select: NM_198503
Type: single nucleotide variant
Location: chr1:196423104 (GRCh38)
Gene constraint: LOEUF 0.744 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.42
Residue 377: the rck n-terminal 1 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.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
KCNT2 p.Tyr708Cys 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-asp377glu (accessed [today's date]).

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