Is KCND2 p.Leu331= (c.993C>A) pathogenic?

KCND2 p.Leu331= (c.993C>A) is classified Likely benign in KCND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). Very rare (popmax 0.00267%, afr); Associated with Early Myoclonic Encephalopathy.

What condition is associated with KCND2 p.Leu331= (c.993C>A)?

KCND2 p.Leu331= (c.993C>A) is associated with Early Myoclonic Encephalopathy (ClinVar).

How common is KCND2 p.Leu331= (c.993C>A) in the general population?

KCND2 p.Leu331= (c.993C>A) is very rare (popmax 0.00267%, afr) (gnomAD).

KCND2 p.Leu331=

c.993C>A · rs1018289599 · VCV1955305

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Early Myoclonic Encephalopathy

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 -0.068	GERP 0.78, phastCons 0.55
Overall
CADD	5.93	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,854 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,610,430 alleles · very rare exomes 2/1,458,396 · genomes 1/152,034 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,427
Finnishnot grpmax-eligible	0.00165%	60,572

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: KCND2
Protein: p.Leu331=
Coding: c.993C>A
MANE Select: NM_012281
dbSNP: rs1018289599
Type: single nucleotide variant
Location: chr7:120275625 (GRCh38)
Gene constraint: LOEUF 0.428 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.28 · 16 PDB
Residue 331: an α-helix

Full KCND2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Early Myoclonic Encephalopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KCND2 p.Pro403Ala Pathogenic/Likely pathogenic ★★ same condition
KCND2 c.1374+3A>G Uncertain significance ★★ same condition
KCND2 c.1468-3C>T Uncertain significance ★★ same condition
KCND2 p.Ala321Val Uncertain significance ★★ ⚠ same condition
KCND2 p.Ala399Ser Uncertain significance ★★ ⚠ same condition
KCND2 p.Arg147His Uncertain significance ★★ ⚠ same condition
KCND2 p.Arg533Ter Uncertain significance ★★ same condition
KCND2 p.Asp153Val 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/kcnd2-p-leu331 (accessed [today's date]).

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