Seckel syndrome 1

Summary

Seckel syndrome 1 (MONDO:0008869) is a disease caused by ATR (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: ATR (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 484

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Seckel syndrome 1
Mondo ID	MONDO:0008869
OMIM	210600
DOID	DOID:0070007
UMLS	C4551474
MedGen	1637056
GARD	0015143
Is cancer (heuristic)	no

Also known as: ATR Seckel syndrome · SCKL1 · Seckel syndrome 1 · Seckel syndrome 3 · Seckel syndrome caused by mutation in ATR · Seckel syndrome type 1

Data availability: 484 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Seckel syndrome › Seckel syndrome 1

Related subtypes (11): intrauterine growth retardation with increased mitomycin c sensitivity, Seckel syndrome 2, Seckel syndrome 4, Seckel syndrome 5, Seckel syndrome 6, Seckel syndrome 7, Seckel syndrome 8, microcephaly 13, primary, autosomal recessive, Seckel syndrome 9, Seckel syndrome 10, Seckel syndrome 11

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

484 retrieved; paginated sample, class counts are floors:

217 uncertain significance, 133 likely benign, 66 conflicting classifications of pathogenicity, 30 benign/likely benign, 19 benign, 7 likely pathogenic, 6 pathogenic, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069016	NM_001184.4(ATR):c.5851C>T (p.Arg1951Ter)	ATR	Pathogenic	criteria provided, multiple submitters, no conflicts
156536	NM_001184.4(ATR):c.3477G>T (p.Met1159Ile)	ATR	Pathogenic	criteria provided, single submitter
156537	NM_001184.4(ATR):c.6897+464C>G	ATR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723224	NM_001184.4(ATR):c.7597C>T (p.Arg2533Ter)	ATR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210488	NM_001184.4(ATR):c.4641+1G>T	ATR	Pathogenic	criteria provided, single submitter
224559	NM_001184.4(ATR):c.4957C>T (p.Arg1653Ter)	ATR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
376356	NM_001184.4(ATR):c.2320del (p.Ile774fs)	ATR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
41901	NM_001184.4(ATR):c.5635G>T (p.Asp1879Tyr)	ATR	Pathogenic	no assertion criteria provided
434454	NM_001184.4(ATR):c.5196+1G>A	ATR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4525892	NC_000003.11:g.(?142168076)(142297576_?)del	ATR	Pathogenic	criteria provided, single submitter
938417	NM_001184.4(ATR):c.2320dup (p.Ile774fs)	ATR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
977841	NM_001184.4(ATR):c.3043C>T (p.Arg1015Ter)	ATR	Pathogenic	criteria provided, single submitter
2712677	NM_001184.4(ATR):c.7042-1G>A	ATR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382387	NM_001184.4(ATR):c.6787C>T (p.Gln2263Ter)	ATR	Likely pathogenic	criteria provided, single submitter
3588636	NM_001184.4(ATR):c.1399A>T (p.Lys467Ter)	ATR	Likely pathogenic	criteria provided, single submitter
3629927	NM_001184.4(ATR):c.3725+2T>C	ATR	Likely pathogenic	criteria provided, single submitter
4531210	NM_001184.4(ATR):c.4912del (p.Gln1638fs)	ATR	Likely pathogenic	criteria provided, single submitter
559542	NM_001184.4(ATR):c.4995G>T (p.Lys1665Asn)	ATR	Likely pathogenic	no assertion criteria provided
559543	NM_001184.4(ATR):c.151+4A>G	ATR	Likely pathogenic	no assertion criteria provided
1034823	NM_001184.4(ATR):c.6800T>C (p.Ile2267Thr)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044519	NM_001184.4(ATR):c.2638G>A (p.Ala880Thr)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1136616	NM_001184.4(ATR):c.3695C>A (p.Ala1232Asp)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1394841	NM_001184.4(ATR):c.1258C>G (p.Leu420Val)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1443597	NM_001184.4(ATR):c.3458A>G (p.Asn1153Ser)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157969	NM_001184.4(ATR):c.2205C>T (p.His735=)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157970	NM_001184.4(ATR):c.2290A>G (p.Lys764Glu)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157972	NM_001184.4(ATR):c.2688G>A (p.Leu896=)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157977	NM_001184.4(ATR):c.3424A>G (p.Ser1142Gly)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157980	NM_001184.4(ATR):c.3799G>A (p.Val1267Ile)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157984	NM_001184.4(ATR):c.4306A>G (p.Asn1436Asp)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · 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
ANTXR1	Definitive	Autosomal recessive	Seckel syndrome 1	16
ATR	Definitive	Autosomal recessive	Seckel syndrome 1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANTXR1	Orphanet:2067	GAPO syndrome
ATR	Orphanet:313846	Familial cutaneous telangiectasia and oropharyngeal cancer predisposition syndrome
ATR	Orphanet:808	Seckel syndrome
CPAP	Orphanet:2512	Autosomal recessive primary microcephaly
CPAP	Orphanet:808	Seckel syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ANTXR1	HGNC:21014	ENSG00000169604	Q9H6X2	Anthrax toxin receptor 1	gencc,clinvar
ATR	HGNC:882	ENSG00000175054	Q13535	Serine/threonine-protein kinase ATR	gencc,clinvar
CPAP	HGNC:17272	ENSG00000151849	Q9HC77	Centrosomal P4.1-associated protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANTXR1	Anthrax toxin receptor 1	Plays a role in cell attachment and migration.
ATR	Serine/threonine-protein kinase ATR	Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor.
CPAP	Centrosomal P4.1-associated protein	Plays an important role in cell division and centrosome function by participating in centriole duplication.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANTXR1	Other/Unknown	no		VWF_A, Anthrax_toxin_rcpt_C, Anthrax_toxin_rcpt_extracel
ATR	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
CPAP	Other/Unknown	no		CENPJ_C_dom, TCP10L/CENPJ, Tcp10_C_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
decidua	1
palpebral conjunctiva	1
stromal cell of endometrium	1
Brodmann (1909) area 23	1
adrenal tissue	1
epithelium of nasopharynx	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANTXR1	270	ubiquitous	marker	stromal cell of endometrium, decidua, palpebral conjunctiva
ATR	289	ubiquitous	marker	Brodmann (1909) area 23, epithelium of nasopharynx, adrenal tissue
CPAP	246	ubiquitous	marker	sperm, left lobe of thyroid gland, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATR	3,541
CPAP	2,242
ANTXR1	2,039

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATR	Q13535	10
CPAP	Q9HC77	6
ANTXR1	Q9H6X2	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 43. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Uptake and function of anthrax toxins	1	317.2×	0.032	ANTXR1
Diseases of DNA Double-Strand Break Repair	1	271.9×	0.032	ATR
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	271.9×	0.032	ATR
Diseases of DNA repair	1	190.3×	0.032	ATR
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	1	173.0×	0.032	CPAP
Cellular response to heat stress	1	131.3×	0.032	ATR
Homologous DNA Pairing and Strand Exchange	1	126.9×	0.032	ATR
Homology Directed Repair	1	102.9×	0.032	ATR
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	102.9×	0.032	ATR
Impaired BRCA2 binding to RAD51	1	102.9×	0.032	ATR
Activation of ATR in response to replication stress	1	100.2×	0.032	ATR
HDR through Single Strand Annealing (SSA)	1	97.6×	0.032	ATR
Meiosis	1	95.2×	0.032	ATR
Fanconi Anemia Pathway	1	92.8×	0.032	ATR
Presynaptic phase of homologous DNA pairing and strand exchange	1	90.6×	0.032	ATR
DNA Double-Strand Break Repair	1	82.8×	0.032	ATR
Reproduction	1	63.4×	0.034	ATR
HDR through Homologous Recombination (HRR)	1	63.4×	0.034	ATR
TP53 Regulates Transcription of DNA Repair Genes	1	60.4×	0.034	ATR
Loss of Nlp from mitotic centrosomes	1	52.9×	0.034	CPAP
Loss of proteins required for interphase microtubule organization from the centrosome	1	52.9×	0.034	CPAP
AURKA Activation by TPX2	1	50.8×	0.034	CPAP
Meiotic synapsis	1	47.0×	0.034	ATR
Regulation of HSF1-mediated heat shock response	1	46.4×	0.034	ATR
Recruitment of mitotic centrosome proteins and complexes	1	45.3×	0.034	CPAP
G2/M Checkpoints	1	44.8×	0.034	ATR
Regulation of TP53 Activity	1	44.3×	0.034	ATR
Regulation of PLK1 Activity at G2/M Transition	1	42.3×	0.034	CPAP
G2/M DNA damage checkpoint	1	40.1×	0.034	ATR
Regulation of TP53 Activity through Phosphorylation	1	39.2×	0.034	ATR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
astral microtubule nucleation	1	5617.3×	0.004	CPAP
establishment of RNA localization to telomere	1	2808.7×	0.004	ATR
establishment of protein-containing complex localization to telomere	1	2808.7×	0.004	ATR
positive regulation of telomerase catalytic core complex assembly	1	2808.7×	0.004	ATR
nuclear membrane disassembly	1	1872.4×	0.005	ATR
centriole elongation	1	1404.3×	0.005	CPAP
negative regulation of extracellular matrix assembly	1	1404.3×	0.005	ANTXR1
positive regulation of centriole replication	1	1123.5×	0.006	CPAP
positive regulation of establishment of protein localization	1	936.2×	0.006	CPAP
positive regulation of centriole elongation	1	802.5×	0.006	CPAP
positive regulation of spindle assembly	1	702.2×	0.006	CPAP
positive regulation of non-motile cilium assembly	1	624.1×	0.007	CPAP
regulation of centriole replication	1	561.7×	0.007	CPAP
protein localization to chromosome, telomeric region	1	510.7×	0.007	ATR
response to arsenic-containing substance	1	401.2×	0.008	ATR
regulation of cellular response to heat	1	351.1×	0.008	ATR
positive regulation of DNA damage response, signal transduction by p53 class mediator	1	330.4×	0.008	ATR
replicative senescence	1	330.4×	0.008	ATR
negative regulation of DNA replication	1	295.6×	0.008	ATR
microtubule polymerization	1	295.6×	0.008	CPAP
regulation of mitotic spindle organization	1	280.9×	0.008	CPAP
mitotic G2/M transition checkpoint	1	267.5×	0.008	ATR
centriole replication	1	244.2×	0.009	CPAP
positive regulation of telomere maintenance via telomerase	1	244.2×	0.009	ATR
microtubule nucleation	1	208.1×	0.009	CPAP
cellular response to gamma radiation	1	200.6×	0.009	ATR
motile cilium assembly	1	193.7×	0.009	CPAP
regulation of double-strand break repair	1	193.7×	0.009	ATR
nucleobase-containing compound metabolic process	1	175.5×	0.010	ATR
positive regulation of epidermal growth factor receptor signaling pathway	1	165.2×	0.010	ANTXR1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATR	8	3
ANTXR1	0	0
CPAP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CERALASERTIB	3	ATR
DACTOLISIB	3	ATR
BERZOSERTIB	2	ATR
CAMONSERTIB	2	ATR
TUVUSERTIB	2	ATR
ELIMUSERTIB	1	ATR
M4344	1	ATR
AEW-541	1	ATR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ATR	231	Binding:226, Functional:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATR	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ATR	231

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

8 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.

Compound	Max phase	Cohort target (bioactivity)
CERALASERTIB	3	ATR
DACTOLISIB	3	ATR
BERZOSERTIB	2	ATR
CAMONSERTIB	2	ATR
TUVUSERTIB	2	ATR
ELIMUSERTIB	1	ATR
M4344	1	ATR
AEW-541	1	ATR

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	1	ATR
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ANTXR1, CPAP

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)
ANTXR1	0	—
CPAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.