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…

MultiplemechanismLOEUF 1.61

Clinical Summary— DUSP2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

59 VUS of 66 total submissions

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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

This gene — mechanism propensity

0.7035th %ile

GOF

0.72top 25%

LOF

0.2775th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction 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

66 submitted variants in ClinVar

ClinVar

Classification Summary

VUS59

Likely Benign1

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	59	0	59
Likely Benign	0	1	1
Benign	0	1	1
Total	59	2	61

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap DUSP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →