SHISA9

Chr 16

shisa family member 9

Also known as: CKAMP44

NCBI Gene: 729993 ENSG00000237515 UniProt: B4DS77 OMIM: 613346

The protein regulates short-term neuronal synaptic plasticity by associating with AMPA glutamate receptors in synaptic spines and promoting their desensitization at excitatory synapses. The gene is highly constrained against loss-of-function variants (pLI 0.87, LOEUF 0.41), but no established human disease associations have been reported to date.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable PDZ domain binding activity. Predicted to be involved in regulation of postsynaptic neurotransmitter receptor activity and regulation of short-term neuronal synaptic plasticity. Predicted to act upstream of or within regulation of AMPA receptor activity. Predicted to be located in synapse. Predicted to be part of AMPA glutamate receptor complex. Predicted to be active in dendritic spine membrane; glutamatergic synapse; and postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.41

Clinical Summary— SHISA9

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.87) — some intolerance to loss-of-function variants.

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ClinVar Variants

61 VUS of 65 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?

0.41LOEUF

pLI 0.873

Z-score 3.18

OE 0.13 (0.05–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.79Z-score

OE missense 0.68 (0.59–0.77)

164 obs / 242.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.05–0.41)

0≤0.351.4

Missense OE?0.68 (0.59–0.77)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 2 / 15.5Missense obs/exp: 164 / 242.4Syn Z: 0.73

This gene — mechanism propensity

0.5378th %ile

GOF

0.6443th %ile

LOF

0.68top 10%

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

LOFprediction above median · LOEUF 0.41

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

65 submitted variants in ClinVar

ClinVar

Classification Summary

VUS61

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	61	61
Likely Benign	2	2
Benign	0	0
Total	63	63

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap SHISA9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →