CNKSR3

Chr 6

CNKSR family member 3

Also known as: CNK3, CNK3/IPCEF1, MAGI1

NCBI Gene: 154043ENSG00000153721UniProt: Q6P9H4OMIM: 617476

CNKSR3 encodes a scaffold protein that regulates epithelial sodium channel (ENaC)-mediated sodium transport by coordinating the assembly of an ENaC-regulatory complex and controlling ENaC cell surface expression. Mutations cause autosomal recessive intellectual disability with seizures and hyponatremia. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.49), suggesting some intolerance to complete protein loss.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.49
Clinical Summary— CNKSR3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.
📋
ClinVar Variants
26 unique Pathogenic / Likely Pathogenic· 79 VUS of 121 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.49LOEUF
pLI 0.028
Z-score 3.74
OE 0.28 (0.17–0.49)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.59Z-score
OE missense 0.91 (0.83–1.00)
301 obs / 331.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.28 (0.17–0.49)
0≤0.351.4
Missense OE0.91 (0.83–1.00)
0≤0.61.4
Synonymous OE0.89
0≤1.21.6
LoF obs/exp: 9 / 31.8Missense obs/exp: 301 / 331.0Syn Z: 0.96
DN
0.74top 25%
GOF
0.72top 25%
LOF
0.4135th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

121 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic3
VUS79
Likely Benign2
Benign2
23
Pathogenic
3
Likely Pathogenic
79
VUS
2
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
23
0
23
Likely Pathogenic
0
0
3
0
3
VUS
1
72
5
1
79
Likely Benign
0
2
0
0
2
Benign
0
0
0
2
2
Total174313109

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CNKSR3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 2 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients