CNKSR3

Chr 6

CNKSR family member 3

Also known as: CNK3, CNK3/IPCEF1, MAGI1

NCBI Gene: 154043 ENSG00000153721 UniProt: Q6P9H4 OMIM: 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.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable protein-macromolecule adaptor activity. Predicted to be involved in several processes, including 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. Located in cytosol. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.49

LOEUF

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in CNKSR3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 95

674 rare PASS variants

Rare truncating (LoF)

1 in 3,000

69 rare PASS variants

Rare synonymous (reference)

1 in 110

304 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CNKSR3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 140	1 in 4,600
South Asian	~43k	1 in 78	1 in 1,300
Remaining (unassigned)	~30k	1 in 85	1 in 3,000
European (Finnish)	~27k	1 in 210	1 in 2,000
Admixed American	~22k	1 in 67	1 in 3,100
African / African American	~21k	1 in 77	1 in 2,800
East Asian	~20k	1 in 86	1 in 2,500
Ashkenazi Jewish	~13k	1 in 400	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 100	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 10 of 13 coding exons well covered in gnomAD exomes; exons 5, 7, 8 marginal. Genomes: all 13.? see exons ↓