Is KCNA1 p.Phe331Ser (c.992T>C) pathogenic?

KCNA1 p.Phe331Ser (c.992T>C) is classified Likely pathogenic in KCNA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.9874); Absent from gnomAD v4.1; Associated with episodic ataxia type 1.

What condition is associated with KCNA1 p.Phe331Ser (c.992T>C)?

KCNA1 p.Phe331Ser (c.992T>C) is associated with episodic ataxia type 1 (ClinVar).

How common is KCNA1 p.Phe331Ser (c.992T>C) in the general population?

KCNA1 p.Phe331Ser (c.992T>C) is absent from gnomAD v4.1 (gnomAD).

How is Episodic ataxia type 1 inherited?

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

What do computational predictors say about KCNA1 p.Phe331Ser (c.992T>C)?

AlphaMissense predicts likely pathogenic (score 0.9874) — an in-silico prediction, not a clinical call.

KCNA1 p.Phe331Ser

c.992T>C · VCV4755548

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9874 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

episodic ataxia type 1

Computational evidence

Protein change
AlphaMissense	0.9874	likely pathogenic ✓ concordant with ClinVar
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -13.34	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 8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 447 bp · p 3.1e-22 · regional, not allelic
Overall
CADD	29.8	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: KCNA1
Protein: p.Phe331Ser
Coding: c.992T>C
MANE Select: NM_000217
Type: single nucleotide variant
Location: chr12:4912370 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.74

Full KCNA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

episodic ataxia type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Episodic ataxia type 1 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood

Similar variants

KCNA1 p.Phe331Cys Uncertain significance ★ ⚠ same residue
KCNA1 p.Phe331Ile Uncertain significance ★ ⚠ same residue
KCNA1 p.Ala166Thr Likely pathogenic ★★ same condition
KCNA1 p.Arg417Ter Pathogenic ★★ same condition
KCNA1 p.Glu283Lys Pathogenic ★★ same condition
KCNA1 p.Gly396Val Pathogenic/Likely pathogenic ★★ same condition
KCNA1 p.Ile262Thr Pathogenic/Likely pathogenic ★★ same condition
KCNA1 p.Ile314Thr 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/kcna1-p-phe331ser (accessed [today's date]).

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