SENP5

Chr 3

SUMO specific peptidase 5

NCBI Gene: 205564 ENSG00000119231 UniProt: Q96HI0 OMIM: 612845

SENP5 encodes a protease that processes SUMO3 proteins to their mature form and removes SUMO2 and SUMO3 modifications from target proteins, functions that are essential for cell division and numerous biological processes. Mutations cause autosomal recessive developmental delay, seizures, and progressive microcephaly with onset in early childhood. This gene is highly constrained against loss-of-function variants, indicating that complete loss of SENP5 function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

The reversible posttranslational modification of proteins by the addition of small ubiquitin-like SUMO proteins (see SUMO1; MIM 601912) is required for numerous biologic processes. SUMO-specific proteases, such as SENP5, are responsible for the initial processing of SUMO precursors to generate a C-terminal diglycine motif required for the conjugation reaction. They also have isopeptidase activity for the removal of SUMO from high molecular mass SUMO conjugates (Di Bacco et al., 2006 [PubMed 16738315]).[supplied by OMIM, Jun 2009]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.19

Clinical Summary— SENP5

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

77 VUS of 98 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 4.99

OE 0.06 (0.02–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.12Z-score

OE missense 0.70 (0.63–0.77)

277 obs / 395.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.19)

0≤0.351.4

Missense OE?0.70 (0.63–0.77)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 2 / 32.9Missense obs/exp: 277 / 395.5Syn Z: -0.03

This gene — mechanism propensity

0.4487th %ile

GOF

0.4678th %ile

LOF

0.67top 25%

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

LOFprediction above median · LOEUF 0.19

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

98 submitted variants in ClinVar

ClinVar

Classification Summary

VUS77

Likely Benign2

Benign4

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	77	0	0	77
Likely Benign	2	0	0	2
Benign	2	1	1	4
Total	81	1	1	83

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

View in ClinVar →

88 pathogenic / likely-pathogenic (of 113) ClinVar copy-number / structural variants overlap SENP5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →