SHISA6

Chr 17

shisa family member 6

NCBI Gene: 388336 ENSG00000188803 UniProt: Q6ZSJ9 OMIM: 617327

The protein regulates AMPA-type glutamate receptor function at synapses, maintaining high-frequency synaptic transmission by preventing receptor immobilization and synaptic depression. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, epilepsy, and progressive microcephaly. The gene is highly constrained against loss-of-function variants, reflecting its critical role in synaptic function.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable ionotropic glutamate receptor binding activity. Predicted to be involved in several processes, including excitatory chemical synaptic transmission; modulation of chemical synaptic transmission; and negative regulation of canonical Wnt signaling pathway. Predicted to be located in asymmetric, glutamatergic, excitatory 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…

LOFmechanismLOEUF 0.40

Clinical Summary— SHISA6

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.85) — 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?

0.40LOEUF

pLI 0.853

Z-score 3.46

OE 0.15 (0.07–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.15Z-score

OE missense 0.65 (0.58–0.73)

197 obs / 302.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.15 (0.07–0.40)

0≤0.351.4

Missense OE?0.65 (0.58–0.73)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 3 / 19.5Missense obs/exp: 197 / 302.3Syn Z: 0.70

This gene — mechanism propensity

0.5869th %ile

GOF

0.6053th %ile

LOF

0.70top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.40

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.