Is KCND3 p.Phe227= (c.681C>T) pathogenic?

KCND3 p.Phe227= (c.681C>T) is classified Likely benign in KCND3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-14). Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with KCND3 p.Phe227= (c.681C>T)?

KCND3 p.Phe227= (c.681C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is KCND3 p.Phe227= (c.681C>T) in the general population?

KCND3 p.Phe227= (c.681C>T) is absent from gnomAD v4.1 (gnomAD).

KCND3 p.Phe227=

c.681C>T · rs2525701650 · VCV1755609

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3	GERP -4.2
Overall
CADD	0.758	PHRED · no single calibrated threshold — expert panels disagree

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.Phe227=
Coding: c.681C>T
MANE Select: NM_001378969
dbSNP: rs2525701650
Type: single nucleotide variant
Location: chr1:111982046 (GRCh38)
Gene constraint: LOEUF 0.303 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.32 · 6 PDB
Residue 227: a UniProt-annotated variant site (in sca19; results in reduced channel activity consistent with impaired cell surface expression of the mutant protein); an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KCND3 p.Phe227del Pathogenic ★★ same residue
KCND3 p.Ala144Thr Uncertain significance ★★ ⚠ same condition
KCND3 p.Ala15Val Uncertain significance ★★ ⚠ same condition
KCND3 p.Ala172Thr Uncertain significance ★★ ⚠ same condition
KCND3 p.Ala30Asp Uncertain significance ★★ ⚠ same condition
KCND3 p.Ala348Val Uncertain significance ★★ ⚠ same condition
KCND3 p.Ala654Thr Uncertain significance ★★ ⚠ same condition
KCND3 p.Arg13Gln 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/kcnd3-p-phe227 (accessed [today's date]).

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