DDR2

Chr 1ARAD

discoidin domain receptor tyrosine kinase 2

Also known as: DDR2-N, MIG20a, NTRKR3, TKT, TYRO10, WRCN

NCBI Gene: 4921ENSG00000162733UniProt: Q16832OMIM: 191311

This gene encodes a member of the discoidin domain receptor subclass of the receptor tyrosine kinase (RTKs) protein family. RTKs play a key role in the communication of cells with their microenvironment. The encoded protein is a collagen-induced receptor that activates signal transduction pathways involved in cell adhesion, proliferation, and extracellular matrix remodeling. This protein is expressed in numerous cell types and may alos be involved in wound repair and regulate tumor growth and invasiveness. Mutations in this gene are the cause of short limb-hand type spondylometaepiphyseal dysplasia. [provided by RefSeq, Aug 2017]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismAR/ADLOEUF 0.382 OMIM phenotypes
Clinical Summary— DDR2
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Gene-Disease Validity (ClinGen)
spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.55) — some intolerance to loss-of-function variants.
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ClinVar Variants
28 unique Pathogenic / Likely Pathogenic· 219 VUS of 482 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — DDR2
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?
0.38LOEUF
pLI 0.550
Z-score 4.70
OE 0.22 (0.13–0.38)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?
2.29Z-score
OE missense 0.70 (0.64–0.77)
324 obs / 462.4 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?
LoF OE?0.22 (0.13–0.38)
0≤0.351.4
Missense OE?0.70 (0.64–0.77)
0≤0.61.4
Synonymous OE?1.09
0≤1.21.6
LoF obs/exp: 9 / 41.8Missense obs/exp: 324 / 462.4Syn Z: -0.87
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongDDR2-related Warburg-Cinotti syndromeOTHERAD
definitiveDDR2-related spondyloepimetaphyseal dysplasia short limb-hand typeOTHERAR

This gene — mechanism propensity

DN
0.5966th %ile
GOF
0.75top 25%
LOF
0.4234th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). 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 · 1 literature citation
LOF68% of P/LP variants are LoF · LOEUF 0.38

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.

Literature Evidence

GOFThese data suggest that gain-of-function mutations in DDR2 are important oncogenic events and are amenable to therapy with dasatinib.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

  1. 1.PMID 22328973 ↗

ClinVar Variant Classifications

482 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic11
VUS219
Likely Benign148
Benign35
Conflicting27
17
Pathogenic
11
Likely Pathogenic
219
VUS
148
Likely Benign
35
Benign
27
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
3
2
0
17
Likely Pathogenic
7
4
0
0
11
VUS
1
190
24
4
219
Likely Benign
0
1
64
83
148
Benign
0
0
31
4
35
Conflicting
—27
Total2019812191457

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap DDR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

DDR2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients