DUSP2

Chr 2

dual specificity phosphatase 2

Also known as: PAC-1, PAC1

NCBI Gene: 1844 ENSG00000158050 UniProt: Q05923 OMIM: 603068

DUSP2 encodes a dual specificity phosphatase that dephosphorylates and inactivates ERK1 and ERK2 MAP kinases, negatively regulating cellular proliferation and differentiation pathways. Mutations cause autosomal recessive intellectual disability with seizures and microcephaly. The gene shows very low constraint to loss-of-function variants (pLI 0.00004), suggesting tolerance to complete loss of function.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the dual specificity protein phosphatase subfamily. These phosphatases inactivate their target kinases by dephosphorylating both the phosphoserine/threonine and phosphotyrosine residues. They negatively regulate members of the mitogen-activated protein (MAP) kinase superfamily (MAPK/ERK, SAPK/JNK, p38), which are associated with cellular proliferation and differentiation. Different members of the family of dual specificity phosphatases show distinct substrate specificities for various MAP kinases, different tissue distribution and subcellular localization, and different modes of inducibility of their expression by extracellular stimuli. This gene product inactivates ERK1 and ERK2, is predominantly expressed in hematopoietic tissues, and is localized in the nucleus. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.61

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.61LOEUF

pLI 0.000

Z-score 0.31

OE 0.88 (0.50–1.61)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.08Z-score

OE missense 0.98 (0.86–1.13)

146 obs / 148.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.88 (0.50–1.61)

0≤0.351.4

Missense OE?0.98 (0.86–1.13)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 7 / 7.9Missense obs/exp: 146 / 148.9Syn Z: 0.42

Background carrier burden — how many people carry a rare variant somewhere in DUSP2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

495 rare PASS variants

Rare truncating (LoF)

1 in 2,700

68 rare PASS variants

Rare synonymous (reference)

1 in 200

254 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DUSP2. 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 170	1 in 2,900
South Asian	~43k	1 in 140	1 in 1,500
Remaining (unassigned)	~30k	1 in 84	≈ 1 in 9,100
European (Finnish)	~27k	1 in 300	≈ 1 in 9,300
Admixed American	~22k	1 in 82	1 in 690
African / African American	~21k	1 in 140	1 in 3,700
East Asian	~20k	1 in 160	1 in 1,700
Ashkenazi Jewish	~13k	1 in 190	≈ 1 in 3,400
Middle Eastern	~2,884	1 in 130	≈ 1 in 740

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 4 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 4.? see exons ↓