Ataxia-pancytopenia syndrome

Summary

Ataxia-pancytopenia syndrome (MONDO:0008038) is a disease caused by SAMD9L (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SAMD9L (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 100
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		25	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001272	Cerebellar atrophy	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0002317	Unsteady gait	Very frequent (80-99%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Very frequent (80-99%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001874	Abnormality of neutrophils	Frequent (30-79%)
HP:0001908	Hypoplastic anemia	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0004311	Abnormal macrophage morphology	Frequent (30-79%)
HP:0004820	Acute myelomonocytic leukemia	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0001876	Pancytopenia	Occasional (5-29%)
HP:0004313	Decreased circulating antibody level	Occasional (5-29%)
HP:0011869	Abnormal platelet function	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ataxia-pancytopenia syndrome
Mondo ID	MONDO:0008038
MeSH	C563233
OMIM	159550
Orphanet	2585
NCIT	C176909
SNOMED CT	768556005
UMLS	C1327919
MedGen	230896
GARD	0003865
Is cancer (heuristic)	no

Also known as: ataxia-pancytopenia syndrome · ATXPC · myelocerebellar disorder

Data availability: 100 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › cerebellar ataxia › hereditary cerebellar ataxia › ataxia-pancytopenia syndrome

Related subtypes (4): ataxia telangiectasia, autosomal recessive cerebellar ataxia, X-linked cerebellar ataxia, autosomal dominant cerebellar ataxia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

100 retrieved; paginated sample, class counts are floors:

65 uncertain significance, 23 conflicting classifications of pathogenicity, 5 benign/likely benign, 3 likely pathogenic, 2 pathogenic, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
242372	NM_152703.5(SAMD9L):c.2640C>A (p.His880Gln)	SAMD9L	Pathogenic	criteria provided, single submitter
446529	NM_152703.5(SAMD9L):c.2672T>C (p.Ile891Thr)	SAMD9L	Pathogenic	no assertion criteria provided
446530	NM_152703.5(SAMD9L):c.2956C>T (p.Arg986Cys)	SAMD9L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2498159	NM_152703.5(SAMD9L):c.[1076G>A;3353A>G]		Likely pathogenic	criteria provided, single submitter
3382574	NM_152703.5(SAMD9L):c.2675T>G (p.Met892Arg)	SAMD9L	Likely pathogenic	criteria provided, single submitter
983121	NM_152703.5(SAMD9L):c.2905A>G (p.Thr969Ala)	SAMD9L	Likely pathogenic	criteria provided, single submitter
1017243	NM_152703.5(SAMD9L):c.4082T>C (p.Val1361Ala)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038336	NM_152703.5(SAMD9L):c.1549T>C (p.Trp517Arg)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1049535	NM_152703.5(SAMD9L):c.208C>T (p.Arg70Cys)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1049582	NM_152703.5(SAMD9L):c.2069G>A (p.Gly690Asp)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1049620	NM_152703.5(SAMD9L):c.2528G>A (p.Arg843Gln)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1063306	NM_152703.5(SAMD9L):c.854G>A (p.Arg285Gln)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1190635	NM_152703.5(SAMD9L):c.2957G>A (p.Arg986His)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1321120	NM_152703.5(SAMD9L):c.3610G>T (p.Gly1204Cys)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1327575	NM_152703.5(SAMD9L):c.4508C>T (p.Thr1503Ile)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1338039	NM_152703.5(SAMD9L):c.2387T>G (p.Ile796Ser)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1398495	NM_152703.5(SAMD9L):c.390A>C (p.Lys130Asn)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1519066	NM_152703.5(SAMD9L):c.4298T>C (p.Leu1433Pro)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1520277	NM_152703.5(SAMD9L):c.4646T>C (p.Ile1549Thr)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2090304	NM_152703.5(SAMD9L):c.3374A>G (p.Gln1125Arg)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2289325	NM_152703.5(SAMD9L):c.829A>G (p.Ile277Val)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3362845	NM_152703.5(SAMD9L):c.4148C>T (p.Ser1383Phe)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3367969	NM_152703.5(SAMD9L):c.2632A>G (p.Lys878Glu)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3775630	NM_152703.5(SAMD9L):c.2107G>T (p.Glu703Ter)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432926	NM_152703.5(SAMD9L):c.1877C>T (p.Ser626Leu)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
624284	NM_152703.5(SAMD9L):c.3353A>G (p.Tyr1118Cys)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
691978	NM_152703.5(SAMD9L):c.2956C>A (p.Arg986Ser)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
774190	NM_152703.5(SAMD9L):c.1216C>T (p.Arg406Ter)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
813694	NM_152703.5(SAMD9L):c.2114A>G (p.Tyr705Cys)	SAMD9L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3602702	NM_017654.4(SAMD9):c.2708A>C (p.Asn903Thr)	SAMD9	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SAMD9L	Definitive	Autosomal dominant	ataxia-pancytopenia syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SAMD9L	Orphanet:2585	Ataxia-pancytopenia syndrome
SAMD9L	Orphanet:619367	SAMD9L-associated autoinflammatory syndrome
SAMD9L	Orphanet:631106	Spinocerebellar ataxia type 49
SAMD9	Orphanet:306658	Familial normophosphatemic tumoral calcinosis
SAMD9	Orphanet:494433	MIRAGE syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SAMD9L	HGNC:1349	ENSG00000177409	Q8IVG5	Sterile alpha motif domain-containing protein 9-like	gencc,clinvar
SAMD9	HGNC:1348	ENSG00000205413	Q5K651	Sterile alpha motif domain-containing protein 9	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SAMD9L	Sterile alpha motif domain-containing protein 9-like	May be involved in endosome fusion.
SAMD9	Sterile alpha motif domain-containing protein 9	Double-stranded nucleic acid binding that acts as an antiviral factor by playing an essential role in the formation of cytoplasmic antiviral granules.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SAMD9L	Other/Unknown	no		SAM, SAM/pointed_sf
SAMD9	Other/Unknown	no		SAM, SAM/pointed_sf, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
leukocyte	1
pancreatic ductal cell	1
amniotic fluid	1
epithelium of esophagus	1
esophagus squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SAMD9L	231	ubiquitous	marker	pancreatic ductal cell, buccal mucosa cell, leukocyte
SAMD9	247	ubiquitous	marker	esophagus squamous epithelium, amniotic fluid, epithelium of esophagus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SAMD9L	1,608
SAMD9	1,316

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SAMD9	Q5K651	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SAMD9L	Q8IVG5	83.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
endosomal vesicle fusion	1	1123.5×	0.002	SAMD9
innate immune response	1	33.6×	0.030	SAMD9

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SAMD9L	0	0
SAMD9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SAMD9L, SAMD9

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SAMD9L	0	—
SAMD9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.