CHP1

Chr 15AR

calcineurin like EF-hand protein 1

Also known as: CHP, SLC9A1BP, SPAX9, Sid470p, p22, p24

NCBI Gene: 11261 ENSG00000187446 UniProt: Q99653 OMIM: 606988

The protein is a calcium-binding cofactor that regulates Na+/H+ exchanger activity at the plasma membrane, controls vesicular trafficking between organelles, and inhibits calcineurin phosphatase activity. Mutations cause spastic ataxia 9, an autosomal recessive disorder affecting movement and coordination. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.535), suggesting some tolerance to functional disruption.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a phosphoprotein that binds to the Na+/H+ exchanger NHE1. This protein serves as an essential cofactor which supports the physiological activity of NHE family members and may play a role in the mitogenic regulation of NHE1. The protein shares similarity with calcineurin B and calmodulin and it is also known to be an endogenous inhibitor of calcineurin activity. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.541 OMIM phenotype

Clinical Summary— CHP1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.63) — some intolerance to loss-of-function variants.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.627

Z-score 2.64

OE 0.17 (0.07–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.26Z-score

OE missense 0.42 (0.33–0.53)

50 obs / 119.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.17 (0.07–0.54)

0≤0.351.4

Missense OE?0.42 (0.33–0.53)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 2 / 11.8Missense obs/exp: 50 / 119.3Syn Z: 0.04

This gene — mechanism propensity

0.6745th %ile

GOF

0.72top 25%

LOF

0.3941th %ile

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

GOFprediction above median

DNprediction 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.