DESI2

Chr 1

desumoylating isopeptidase 2

Also known as: C1orf121, CGI-146, DeSI-2, FAM152A, PNAS-4, PPPDE1

NCBI Gene: 51029 ENSG00000121644 UniProt: Q9BSY9

The protein functions as a deubiquitinase that removes ubiquitin chains from target proteins and exhibits palmitoyl protein thioesterase activity that removes palmitoyl groups from proteins. Mutations cause autosomal recessive neurodegeneration with brain iron accumulation, typically presenting in childhood with progressive movement disorders and cognitive decline. The gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely pathogenic.

ResearchSummary from RefSeq, UniProt

Enables deubiquitinase activity and long-chain fatty acyl-CoA hydrolase activity. Predicted to be involved in macromolecule depalmitoylation and proteolysis. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.45

LOEUF

—

Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.45LOEUF

pLI 0.848

Z-score 2.73

OE 0.09 (0.03–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.91Z-score

OE missense 0.48 (0.39–0.61)

52 obs / 107.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.09 (0.03–0.45)

0≤0.351.4

Missense OE?0.48 (0.39–0.61)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 1 / 10.6Missense obs/exp: 52 / 107.9Syn Z: 0.31

Background carrier burden — how many people carry a rare variant somewhere in DESI2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 760

159 rare PASS variants

Rare truncating (LoF)

1 in 3,300

27 rare PASS variants

Rare synonymous (reference)

1 in 570

86 rare PASS variants

Rare missense and truncating variants are carried at similar rates in DESI2; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 860	1 in 5,600
South Asian	~43k	1 in 560	1 in 860
Remaining (unassigned)	~30k	1 in 870	none seen
European (Finnish)	~27k	≈ 1 in 5,400	none seen
Admixed American	~22k	1 in 350	≈ 1 in 13,000
African / African American	~21k	1 in 360	none seen
East Asian	~20k	1 in 520	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 560	none seen
Middle Eastern	~2,884	1 in 220	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 3 of 5 coding exons well covered in gnomAD exomes; exons 2, 3 marginal. Genomes: all 5.? see exons ↓