SEZ6L

Chr 22

seizure related 6 homolog like

Also known as: SEZ6L1

NCBI Gene: 23544 ENSG00000100095 UniProt: Q9BYH1 OMIM: 607021

The SEZ6L protein contributes to specialized endoplasmic reticulum functions in neurons and is predicted to be involved in synapse maturation and cerebellar Purkinje cell development. Mutations cause autosomal recessive neurodevelopmental disorders affecting the cerebellum and movement. The gene shows significant constraint against loss-of-function variants (LOEUF 0.37), suggesting intolerance to protein disruption.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to be involved in synapse maturation. Predicted to act upstream of or within activation of protein kinase C activity; adult locomotory behavior; and cerebellar Purkinje cell layer development. Predicted to be located in endoplasmic reticulum membrane. Predicted to be active in several cellular components, including glutamatergic synapse; neuronal cell body; and postsynaptic membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.37

Clinical Summary— SEZ6L

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.51) — some intolerance to loss-of-function variants.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 166 VUS of 200 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.37LOEUF

pLI 0.507

Z-score 4.90

OE 0.22 (0.13–0.37)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.47Z-score

OE missense 0.83 (0.77–0.90)

495 obs / 595.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.13–0.37)

0≤0.351.4

Missense OE?0.83 (0.77–0.90)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 10 / 45.7Missense obs/exp: 495 / 595.9Syn Z: -0.09

This gene — mechanism propensity

0.5966th %ile

GOF

0.6930th %ile

LOF

0.4726th %ile

The highest-scoring mechanism for this gene is gain-of-function.

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

200 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS166

Likely Benign12

Benign7

Likely Pathogenic

166

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	0	0	0	1
VUS	1	164	1	0	166
Likely Benign	0	7	1	4	12
Benign	0	2	1	4	7
Total	2	173	3	8	186

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap SEZ6L — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →