Is KCNC3 p.Phe448Leu (c.1344C>A) pathogenic?

KCNC3 p.Phe448Leu (c.1344C>A) is classified Pathogenic in KCNC3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2006-04-01). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with spinocerebellar ataxia type 13.

What condition is associated with KCNC3 p.Phe448Leu (c.1344C>A)?

KCNC3 p.Phe448Leu (c.1344C>A) is associated with spinocerebellar ataxia type 13 (ClinVar).

How common is KCNC3 p.Phe448Leu (c.1344C>A) in the general population?

KCNC3 p.Phe448Leu (c.1344C>A) is absent from gnomAD v4.1 (gnomAD).

How is Spinocerebellar ataxia type 13 inherited?

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

What do computational predictors say about KCNC3 p.Phe448Leu (c.1344C>A)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

KCNC3 p.Phe448Leu

c.1344C>A · rs104894700 · VCV13474

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia type 13

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic ✓ concordant with ClinVar · top 8% in KCNC3
REVEL	0.696	pathogenic-leaning
SaProt	LLR -12.18	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 4.5	GERP -3.9, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 4,754 bp · p 1.6e-15 · regional, not allelic
Overall
CADD	24.6	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: KCNC3
Protein: p.Phe448Leu
Coding: c.1344C>A
MANE Select: NM_004977
dbSNP: rs104894700
Type: single nucleotide variant
Location: chr19:50323609 (GRCh38)
Gene constraint: LOEUF 0.654 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 66.01
Residue 448: a UniProt-annotated variant site (in sca13; alters gating; slows channel closing; decreases protein abundance; no effect on localization to the plasma membrane; no effect on n-glycosylation; no effect on tetramerization)

Full KCNC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spinocerebellar ataxia type 13 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spinocerebellar ataxia type 13 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

KCNC3 p.Arg420His Pathogenic ★★ same condition
KCNC3 p.Arg423His Pathogenic ★★ same condition
KCNC3 p.Ala749Thr Uncertain significance ★★ ⚠ same condition
KCNC3 p.Gly231Ser Uncertain significance ★★ ⚠ same condition
KCNC3 p.Gly251Ser Uncertain significance ★★ ⚠ same condition
KCNC3 p.Gly331Arg Uncertain significance ★★ ⚠ same condition
KCNC3 p.Gly47Asp Uncertain significance ★★ ⚠ same condition
KCNC3 p.Ile492Val 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/kcnc3-p-phe448leu (accessed [today's date]).

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