SAMD9

Chr 7ADAR

sterile alpha motif domain containing 9

NCBI Gene: 54809ENSG00000205413UniProt: Q5K651

Double-stranded nucleic acid binding that acts as an antiviral factor by playing an essential role in the formation of cytoplasmic antiviral granules (PubMed:25428864, PubMed:28157624). May play a role in the inflammatory response to tissue injury and the control of extra-osseous calcification, acting as a downstream target of TNF signaling. Involved in the regulation of EGR1, in coordination with RGL2. May be involved in endosome fusion

Primary Disease Associations & Inheritance

MIRAGE syndromeMIM #617053
AD
Monosomy 7 myelodysplasia and leukemia syndrome 2MIM #619041
AD
Tumoral calcinosis, familial, normophosphatemicMIM #610455
AR
694
ClinVar variants
2
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— SAMD9
🧬
Gene-Disease Validity (ClinGen)
normophosphatemic familial tumoral calcinosis · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
2 Pathogenic / Likely Pathogenic· 480 VUS of 694 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.24LOEUF
pLI 0.000
Z-score 0.10
OE 0.98 (0.79–1.24)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.77Z-score
OE missense 0.92 (0.87–0.98)
709 obs / 769.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.98 (0.79–1.24)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.87–0.98)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 51 / 51.8Missense obs/exp: 709 / 769.0Syn Z: 0.08

ClinVar Variant Classifications

694 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic2
VUS480
Likely Benign211
Benign1
2
Likely Pathogenic
480
VUS
211
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
0
0
0
Likely Pathogenic
0
2
0
0
2
VUS
6
460
14
0
480
Likely Benign
0
18
0
193
211
Benign
0
1
0
0
1
Total648114193694

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

View in ClinVar →

Protein Context — Lollipop Plot

SAMD9 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SAMD9-related myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, enteropathy (MIRAGE)

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

MIRAGE syndrome

MIM #617053

Molecular basis of disorder known

Autosomal dominant

Monosomy 7 myelodysplasia and leukemia syndrome 2

MIM #619041

Molecular basis of disorder known

Autosomal dominant

Tumoral calcinosis, familial, normophosphatemic

MIM #610455

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — SAMD9
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic and clinical spectrum of SAMD9 and SAMD9L syndromes: from variant interpretation to patient management.
Sahoo SS et al.·Blood
2025Review
Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes.
Sahoo SS et al.·Nat Med
2021
How I treat myelodysplastic syndromes of childhood.
Locatelli F et al.·Blood
2018Review
The International Consensus Classification (ICC) of hematologic neoplasms with germline predisposition, pediatric myelodysplastic syndrome, and juvenile myelomonocytic leukemia.
Rudelius M et al.·Virchows Arch
2023Review
A landscape of germ line mutations in a cohort of inherited bone marrow failure patients.
Bluteau O et al.·Blood
2018Cohort
Inherited Predispositions to Myeloid Neoplasms: Pathogenesis and Clinical Implications.
Liu YC et al.·Annu Rev Pathol
2025Review
Germline and somatic genetic landscape of pediatric myelodysplastic syndromes.
Kotmayer L et al.·Haematologica
2025Review
SAMD9 senses cytosolic double-stranded nucleic acids in epithelial and mesenchymal cells to induce antiviral immunity.
Hou G et al.·Nat Commun
2025
Human SAMD9 is a poxvirus-activatable anticodon nuclease inhibiting codon-specific protein synthesis.
Zhang F et al.·Sci Adv
2023
SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies.
Davidsson J et al.·Leukemia
2018Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Identification of SAMD9 as an adaptive response gene to environmental changes and its association with overall survival and immunotherapeutic response in glioblastoma.
Li F et al.·Cancer Cell Int
2025🔓 Open Access
Normal Immune Function in a Newborn With Early Identification of a SAMD9 Mutation Presenting With Growth Restriction, Thrombocytopenia, and Primary Adrenal Insufficiency.
Gao KM et al.·Clin Case Rep
2025🔓 Open Access
Evolutionary characterization of antiviral SAMD9/9L across kingdoms supports ancient convergence and lineage-specific adaptations.
Legrand A et al.·Nat Ecol Evol
2025🔓 Open Access
Structural and functional studies of rabbit SAMD9 reveal a distinct tRNase module that underlies the antiviral activity.
Chaturvedi J et al.·PLoS Pathog
2025🔓 Open AccessFunctional
Poxvirus Host-Range Determinants: SAMD9/9L and Beyond.
Xiang Y.·Annu Rev Virol
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING
NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21
NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies

External Resources

Links to major genomics databases and tools