Is KCND3 p.Pro355Ser (c.1063C>T) pathogenic?

KCND3 p.Pro355Ser (c.1063C>T) is classified Uncertain significance in KCND3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-03). AlphaMissense: likely pathogenic (0.999); Absent from gnomAD v4.1.

How common is KCND3 p.Pro355Ser (c.1063C>T) in the general population?

KCND3 p.Pro355Ser (c.1063C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KCND3 p.Pro355Ser (c.1063C>T)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

KCND3 p.Pro355Ser

c.1063C>T · rs2101994784 · VCV1319064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -15.39	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 201 kb · p 7.2e-33 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

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: KCND3
Protein: p.Pro355Ser
Coding: c.1063C>T
MANE Select: NM_001378969
dbSNP: rs2101994784
Type: single nucleotide variant
Location: chr1:111981664 (GRCh38)
Gene constraint: LOEUF 0.303 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.32 · 6 PDB

Full KCND3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KCND3 p.Pro355Leu Uncertain significance ★ ⚠ same residue
KCND3 p.Pro355= Likely benign ★ same residue
KCND3 p.Arg290Gln Likely pathogenic ★★ same type
KCND3 p.Gly384Ser Pathogenic/Likely pathogenic ★★ same type
KCND3 p.Pro375Ser Pathogenic/Likely pathogenic ★★ same type
KCND3 p.Thr377Met Pathogenic ★★ same type
KCND3 p.Val392Ile Pathogenic/Likely pathogenic ★★ same type
KCND3 p.Ala144Thr Uncertain significance ★★ ⚠ same type

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/kcnd3-p-pro355ser (accessed [today's date]).

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