Is KCNA2 p.Arg294Pro (c.881G>C) pathogenic?

KCNA2 p.Arg294Pro (c.881G>C) is classified Likely pathogenic in KCNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 32.

What condition is associated with KCNA2 p.Arg294Pro (c.881G>C)?

KCNA2 p.Arg294Pro (c.881G>C) is associated with developmental and epileptic encephalopathy, 32 (ClinVar).

How common is KCNA2 p.Arg294Pro (c.881G>C) in the general population?

KCNA2 p.Arg294Pro (c.881G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KCNA2 p.Arg294Pro (c.881G>C)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

KCNA2 p.Arg294Pro

Q: How is Non-specific early-onset epileptic encephalopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.881G>C · rs886041761 · VCV2109320

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 32

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic ✓ concordant with ClinVar
REVEL	0.979	strongly pathogenic-leaning
SaProt	LLR -16.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 387 bp · p 3e-20 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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: KCNA2
Protein: p.Arg294Pro
Coding: c.881G>C
MANE Select: NM_004974
dbSNP: rs886041761
Type: single nucleotide variant
Location: chr1:110603902 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI 0.94 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.01

Full KCNA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 32 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific early-onset epileptic encephalopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Infancy, Neonatal

Similar variants

KCNA2 p.Arg294His Pathogenic/Likely pathogenic ★★ same residue
KCNA2 p.Arg294Cys Uncertain significance ★ ⚠ same residue
KCNA2 p.Ala262Val Pathogenic/Likely pathogenic ★★ same condition
KCNA2 p.Arg297Gln Pathogenic ★★ same condition
KCNA2 p.Arg297Trp Pathogenic ★★ same condition
KCNA2 p.Gln213Ter Pathogenic ★★ same condition
KCNA2 p.Gly338Glu Pathogenic/Likely pathogenic ★★ same condition
KCNA2 p.Pro405Leu 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/kcna2-p-arg294pro (accessed [today's date]).

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