Is KCND3 p.Phe74= (c.222C>T) pathogenic?

KCND3 p.Phe74= (c.222C>T) is classified Likely benign in KCND3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-29). Very rare (popmax 0.000766%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with KCND3 p.Phe74= (c.222C>T)?

KCND3 p.Phe74= (c.222C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is KCND3 p.Phe74= (c.222C>T) in the general population?

KCND3 p.Phe74= (c.222C>T) is very rare (popmax 0.000766%, nfe) (gnomAD).

KCND3 p.Phe74=

c.222C>T · VCV3862696

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000766%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5	GERP 1.1, phastCons 1
Overall
CADD	10.55	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000766% European (non-Finnish) · 9/1,175,030 alleles

Filtering AF 0.00036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.00056% 9/1,607,732 alleles · very rare exomes 9/1,455,392 · genomes 0/152,340 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: KCND3
Protein: p.Phe74=
Coding: c.222C>T
MANE Select: NM_001378969
Type: single nucleotide variant
Location: chr1:111982505 (GRCh38)
Gene constraint: LOEUF 0.303 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.32 · 6 PDB
Residue 74: the 'interaction with kcnip1' region; a β-strand

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.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
KCND3 p.Arg293His 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-phe74 (accessed [today's date]).

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