Immunodeficiency 64

Summary

Immunodeficiency 64 (MONDO:0032803) is a disease caused by RASGRP1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: RASGRP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 26

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 64
Mondo ID	MONDO:0032803
OMIM	618534
Orphanet	664699
DOID	DOID:0111980
UMLS	C5231402
MedGen	1684716
GARD	0016360
Is cancer (heuristic)	no

Also known as: IMD64

Data availability: 26 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › immunodeficiency 64

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 14b, autosomal recessive, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

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

26 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 8 pathogenic, 4 benign/likely benign, 3 pathogenic/likely pathogenic, 1 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323520	NM_005739.4(RASGRP1):c.327-1C>G	RASGRP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3013600	NM_005739.4(RASGRP1):c.2196_2199del (p.Ser732_Leu733insTer)	RASGRP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3769164	NM_005739.4(RASGRP1):c.1232_1233del (p.His411fs)	RASGRP1	Pathogenic	criteria provided, single submitter
4076366	NM_005739.4(RASGRP1):c.241C>T (p.Arg81Ter)	RASGRP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4537509	NM_005739.4(RASGRP1):c.1720+1G>A	RASGRP1	Pathogenic	criteria provided, single submitter
4538511	NM_005739.4(RASGRP1):c.1720+2T>C	RASGRP1	Pathogenic	criteria provided, single submitter
666277	NM_005739.4(RASGRP1):c.736C>T (p.Arg246Ter)	RASGRP1	Pathogenic	no assertion criteria provided
666278	NM_005739.4(RASGRP1):c.771G>A (p.Trp257Ter)	RASGRP1	Pathogenic	no assertion criteria provided
666279	NM_005739.4(RASGRP1):c.641C>T (p.Thr214Ile)	RASGRP1	Pathogenic	no assertion criteria provided
666280	NM_005739.4(RASGRP1):c.964A>T (p.Lys322Ter)	RASGRP1	Pathogenic	no assertion criteria provided
666281	NM_005739.4(RASGRP1):c.1910_1911insAG (p.Ala638fs)	RASGRP1	Pathogenic	no assertion criteria provided
2431603	NM_005739.4(RASGRP1):c.1418_1428+3del	RASGRP1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341863	NM_005739.4(RASGRP1):c.1199C>A (p.Ala400Asp)	RASGRP1	Uncertain significance	criteria provided, single submitter
1415415	NM_005739.4(RASGRP1):c.1159T>C (p.Tyr387His)	RASGRP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1675118	NM_005739.4(RASGRP1):c.1023G>A (p.Arg341=)	RASGRP1	Uncertain significance	criteria provided, single submitter
1803842	NM_005739.4(RASGRP1):c.1385C>T (p.Pro462Leu)	RASGRP1	Uncertain significance	criteria provided, single submitter
2500074	NM_005739.4(RASGRP1):c.1321C>T (p.Pro441Ser)	RASGRP1	Uncertain significance	criteria provided, single submitter
2502218	NM_005739.4(RASGRP1):c.2163G>T (p.Lys721Asn)	RASGRP1	Uncertain significance	criteria provided, single submitter
3065919	NM_005739.4(RASGRP1):c.1147C>A (p.Leu383Ile)	RASGRP1	Uncertain significance	criteria provided, single submitter
4076365	NM_005739.4(RASGRP1):c.1429-258G>C	RASGRP1	Uncertain significance	criteria provided, single submitter
982603	NM_005739.4(RASGRP1):c.1592C>G (p.Ser531Ter)	RASGRP1	Uncertain significance	criteria provided, single submitter
1165387	NM_005739.4(RASGRP1):c.676-16G>T	RASGRP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1169062	NM_005739.4(RASGRP1):c.1011C>T (p.Tyr337=)	RASGRP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1169063	NM_005739.4(RASGRP1):c.429C>T (p.Asp143=)	RASGRP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1169965	NM_005739.4(RASGRP1):c.1485T>C (p.Phe495=)	RASGRP1	Benign	criteria provided, multiple submitters, no conflicts
1564870	NM_005739.4(RASGRP1):c.876T>C (p.Asn292=)	RASGRP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
RASGRP1	Strong	Autosomal recessive	immunodeficiency 64	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RASGRP1	Orphanet:664699	EBV-induced lymphoproliferative disease due to RASGRP1 deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RASGRP1	HGNC:9878	ENSG00000172575	O95267	RAS guanyl-releasing protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RASGRP1	RAS guanyl-releasing protein 1	Functions as a calcium- and diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RASGRP1	Other/Unknown	no		Ras-like_Gua-exchang_fac_N, RASGEF_cat_dom, EF_hand_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
cerebellar vermis	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RASGRP1	248	broad	marker	pons, cerebellar vermis, Brodmann (1909) area 23

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RASGRP1	1,939

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RASGRP1	O95267	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Activation of RAS in B cells	1	2284.0×	0.003	RASGRP1
Rap1 signalling	1	713.8×	0.004	RASGRP1
Effects of PIP2 hydrolysis	1	456.8×	0.004	RASGRP1
Integrin signaling	1	423.0×	0.004	RASGRP1
FCERI mediated NF-kB activation	1	156.4×	0.008	RASGRP1
RAF/MAP kinase cascade	1	61.1×	0.016	RASGRP1

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
secretory granule localization	1	5617.3×	0.003	RASGRP1
positive regulation of natural killer cell differentiation	1	1685.2×	0.003	RASGRP1
positive regulation of T cell differentiation in thymus	1	1532.0×	0.003	RASGRP1
inflammatory response to antigenic stimulus	1	936.2×	0.003	RASGRP1
positive regulation of Ras protein signal transduction	1	887.0×	0.003	RASGRP1
vesicle transport along microtubule	1	887.0×	0.003	RASGRP1
activation of GTPase activity	1	732.7×	0.003	RASGRP1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	702.2×	0.003	RASGRP1
positive regulation of MAP kinase activity	1	648.1×	0.003	RASGRP1
mast cell degranulation	1	624.1×	0.003	RASGRP1
natural killer cell activation	1	581.1×	0.003	RASGRP1
regulation of ERK1 and ERK2 cascade	1	581.1×	0.003	RASGRP1
positive regulation of natural killer cell mediated cytotoxicity	1	561.7×	0.003	RASGRP1
B cell proliferation	1	481.5×	0.003	RASGRP1
B cell activation	1	455.5×	0.003	RASGRP1
T cell proliferation	1	383.0×	0.003	RASGRP1
positive regulation of protein phosphorylation	1	276.3×	0.004	RASGRP1
T cell activation	1	259.3×	0.004	RASGRP1
Ras protein signal transduction	1	205.5×	0.005	RASGRP1
cell differentiation	1	29.1×	0.036	RASGRP1
signal transduction	1	16.1×	0.062	RASGRP1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RASGRP1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RASGRP1	8	Binding:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	RASGRP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RASGRP1	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.