Is KCNN2 p.Pro40Ser (c.118C>T) pathogenic?

KCNN2 p.Pro40Ser (c.118C>T) is classified Uncertain significance in KCNN2 (ClinVar, Single submitter, 1 submitter). Ultra-rare (popmax 0.0133%, sas); Associated with neurodevelopmental disorder with or without variable movement or behavioral abnormalities.

How common is KCNN2 p.Pro40Ser (c.118C>T) in the general population?

KCNN2 p.Pro40Ser (c.118C>T) is ultra-rare (popmax 0.0133%, sas) (gnomAD).

KCNN2 p.Pro40Ser

Q: What condition is associated with KCNN2 p.Pro40Ser (c.118C>T)?

KCNN2 p.Pro40Ser (c.118C>T) is associated with neurodevelopmental disorder with or without variable movement or behavioral abnormalities (ClinVar).

c.118C>T · VCV4086177

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, sas)

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 4.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.47	unconstrained · MANE · 967 bp · p 3.7e-14 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% South Asian · 1/7,516 alleles

Overall 0.000657% 1/152,188 alleles · ultra-rare

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: KCNN2
Protein: p.Pro40Ser
Coding: c.118C>T
MANE Select: NM_021614
Type: single nucleotide variant
Location: chr5:114362257 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 77.98 · 16 PDB
Residue 40: the 'disordered' region

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.Pro40His Uncertain significance ★ same residue
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

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-pro40ser (accessed [today's date]).

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