CNKSR3

Chr 6

CNKSR family member 3

Also known as: CNK3, CNK3/IPCEF1, MAGI1

NCBI Gene: 154043 ENSG00000153721 UniProt: Q6P9H4

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.

ResearchSummary from RefSeq, UniProt

Predicted to be involved in negative regulation of ERK1 and ERK2 cascade; negative regulation of peptidyl-serine phosphorylation; and positive regulation of sodium ion transport. Predicted to act upstream of or within positive regulation of sodium ion transmembrane transporter activity. Predicted to be located in apical plasma membrane and cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.49

Clinical Summary— CNKSR3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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ClinVar Variants

74 VUS of 90 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.28 (0.17–0.49)

0≤0.351.4

Missense OE?0.91 (0.83–1.00)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 9 / 31.8Missense obs/exp: 301 / 331.0Syn Z: 0.96

This gene — mechanism propensity

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

90 submitted variants in ClinVar

ClinVar

Classification Summary

VUS74

Likely Benign2

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	1	72	1	74
Likely Benign	0	2	0	2
Benign	0	0	2	2
Total	1	74	3	78

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap CNKSR3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →