Is KCNN2 p.Ser74Phe (c.221C>T) pathogenic?

KCNN2 p.Ser74Phe (c.221C>T) is classified Uncertain significance in KCNN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-31). Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with or without variable movement or behavioral abnormalities.

How common is KCNN2 p.Ser74Phe (c.221C>T) in the general population?

KCNN2 p.Ser74Phe (c.221C>T) is absent from gnomAD v4.1 (gnomAD).

KCNN2 p.Ser74Phe

Q: What condition is associated with KCNN2 p.Ser74Phe (c.221C>T)?

KCNN2 p.Ser74Phe (c.221C>T) is associated with neurodevelopmental disorder with or without variable movement or behavioral abnormalities (ClinVar).

c.221C>T · VCV4881123

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

neurodevelopmental disorder with or without variable movement or behavioral abnormalities

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 5.8	GERP -0.21, phastCons 1
Regional constraint	o/e 1.47	unconstrained · MANE · 967 bp · p 3.7e-14 · regional, not allelic
Overall
CADD	23.5	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: KCNN2
Protein: p.Ser74Phe
Coding: c.221C>T
MANE Select: NM_021614
Type: single nucleotide variant
Location: chr5:114362360 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 77.98 · 16 PDB

Full KCNN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with or without variable movement or behavioral abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KCNN2 p.Tyr573Cys Pathogenic/Likely pathogenic ★★ same condition
KCNN2 p.Gln15Ter Uncertain significance ★★ same condition
KCNN2 p.Leu644Pro Pathogenic ★ same condition
KCNN2 p.Ser183Ter Likely pathogenic ★ same condition
KCNN2 p.Trp562Leu Likely pathogenic ★ same condition
KCNN2 p.Tyr372Ter Pathogenic ★ same condition
KCNN2 p.Arg745Gly Uncertain significance ★ ⚠ same condition
KCNN2 p.Arg769Gln 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/kcnn2-p-ser74phe (accessed [today's date]).

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