Rafiq syndrome

Summary

Rafiq syndrome (MONDO:0013624) is a disease caused by MAN1B1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: MAN1B1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 453

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Rafiq syndrome
Mondo ID	MONDO:0013624
OMIM	614202
DOID	DOID:0081097
UMLS	C3280127
MedGen	481757
GARD	0022550
Is cancer (heuristic)	no

Also known as: autosomal recessive non-syndromic intellectual disability caused by mutation in MAN1B1 · CDG2U · intellectual disability, autosomal recessive 15 · MAN1B1 autosomal recessive non-syndromic intellectual disability · mental retardation, autosomal recessive 15 · mental retardation, autosomal recessive type 15 · MRT15 · RAFQS

Data availability: 453 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal recessive non-syndromic intellectual disability › Rafiq syndrome

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 2, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, intellectual disability, autosomal recessive 5, intellectual disability, autosomal recessive 6, intellectual disability, autosomal recessive 7, intellectual disability, autosomal recessive 9, intellectual disability, autosomal recessive 10, intellectual disability, autosomal recessive 11, intellectual disability, autosomal recessive 4, intellectual disability, autosomal recessive 13, intellectual disability, autosomal recessive 14, intellectual disability, autosomal recessive 16, intellectual disability, autosomal recessive 18, intellectual disability, autosomal recessive 31, intellectual disability, autosomal recessive 29, intellectual disability, autosomal recessive 27, intellectual disability, autosomal recessive 33, intellectual disability, autosomal recessive 30, intellectual disability, autosomal recessive 19, intellectual disability, autosomal recessive 23, intellectual disability, autosomal recessive 24, intellectual disability, autosomal recessive 25, intellectual disability, autosomal recessive 28, intellectual disability, autosomal recessive 34, intellectual disability, autosomal recessive 42, intellectual disability, autosomal recessive 43, intellectual disability, autosomal recessive 44, intellectual disability, autosomal recessive 45, intellectual disability, autosomal recessive 46, intellectual disability, autosomal recessive 47, Al-Raqad syndrome, intellectual disability, autosomal recessive 50, intellectual disability, autosomal recessive 51, intellectual disability, autosomal recessive 52, intellectual disability, autosomal recessive 54, intellectual disability, autosomal recessive 56, intellectual developmental disorder, autosomal recessive 74, intellectual disability, autosomal recessive 57, intellectual disability, autosomal recessive 58, intellectual disability, autosomal recessive 59, pontocerebellar hypoplasia type 1, intellectual disability, autosomal recessive 64, intellectual disability, autosomal recessive 65, intellectual developmental disorder, autosomal recessive 73, intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, intellectual disability, autosomal recessive 61, intellectual developmental disorder, autosomal recessive 76, intellectual developmental disorder, autosomal recessive 77, intellectual disability, autosomal recessive 66, intellectual developmental disorder, autosomal recessive 67, intellectual developmental disorder, autosomal recessive 68, intellectual developmental disorder, autosomal recessive 69, intellectual developmental disorder, autosomal recessive 70, intellectual developmental disorder, autosomal recessive 71, intellectual developmental disorder, autosomal recessive 72, glycosylphosphatidylinositol biosynthesis defect 16, intellectual disability, autosomal recessive 60, intellectual disability, autosomal recessive 63, adenosine kinase deficiency, intellectual developmental disorder, autosomal recessive 78, intellectual developmental disorder, autosomal recessive 79, intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, intellectual developmental disorder, autosomal recessive 81, intellectual developmental disorder, autosomal recessive 82, intellectual developmental disorder, autosomal recessive 83

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

453 retrieved; paginated sample, class counts are floors:

169 likely benign, 153 uncertain significance, 49 conflicting classifications of pathogenicity, 28 pathogenic, 21 benign, 18 benign/likely benign, 12 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2423367	NC_000009.11:g.(?139089171)(141016451_?)del	ABCA2	Pathogenic	criteria provided, single submitter
802546	NM_016219.5(MAN1B1):c.179dup (p.Tyr60Ter)	LOC130003079	Pathogenic	criteria provided, single submitter
816942	NM_016219.5(MAN1B1):c.172G>T (p.Glu58Ter)	LOC130003079	Pathogenic	criteria provided, multiple submitters, no conflicts
983294	NM_016219.5(MAN1B1):c.465+1462_620+529del	LOC130003080	Pathogenic	no assertion criteria provided
1030542	NM_016219.5(MAN1B1):c.1444C>T (p.Gln482Ter)	MAN1B1	Pathogenic	criteria provided, single submitter
1076605	NM_016219.5(MAN1B1):c.242T>A (p.Leu81Ter)	MAN1B1	Pathogenic	criteria provided, single submitter
1207945	NM_016219.5(MAN1B1):c.1735dup (p.Gln579fs)	MAN1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1254598	NM_016219.5(MAN1B1):c.484C>T (p.Gln162Ter)	MAN1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1458149	NC_000009.11:g.(?139981452)(139983477_?)del	MAN1B1	Pathogenic	criteria provided, single submitter
1691271	NM_016219.5(MAN1B1):c.1075G>T (p.Gly359Ter)	MAN1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2012254	NM_016219.5(MAN1B1):c.772_775del (p.Leu258fs)	MAN1B1	Pathogenic	criteria provided, single submitter
203378	NM_016219.5(MAN1B1):c.1276_1277del (p.Gln426fs)	MAN1B1	Pathogenic	criteria provided, single submitter
2087749	NM_016219.5(MAN1B1):c.1236_1237del (p.Gly413_Asp414insTer)	MAN1B1	Pathogenic	criteria provided, single submitter
2115404	NM_016219.5(MAN1B1):c.1228del (p.Arg410fs)	MAN1B1	Pathogenic	criteria provided, single submitter
2579642	NM_016219.5(MAN1B1):c.624G>A (p.Trp208Ter)	MAN1B1	Pathogenic	criteria provided, single submitter
2791167	NM_016219.5(MAN1B1):c.1241del (p.Asp414fs)	MAN1B1	Pathogenic	criteria provided, single submitter
3014905	NM_016219.5(MAN1B1):c.1397_1398del (p.Tyr465_Tyr466insTer)	MAN1B1	Pathogenic	criteria provided, single submitter
30414	NM_016219.5(MAN1B1):c.1418G>A (p.Trp473Ter)	MAN1B1	Pathogenic	criteria provided, single submitter
3245243	NC_000009.11:g.(?139981452)(140003043_?)del	MAN1B1	Pathogenic	criteria provided, single submitter
3363104	NM_016219.5(MAN1B1):c.2065G>T (p.Glu689Ter)	MAN1B1	Pathogenic	criteria provided, single submitter
3701326	NM_016219.5(MAN1B1):c.1731C>G (p.Tyr577Ter)	MAN1B1	Pathogenic	criteria provided, single submitter
3716972	NM_016219.5(MAN1B1):c.1177_1178dup (p.Ser393fs)	MAN1B1	Pathogenic	criteria provided, single submitter
4703323	NM_016219.5(MAN1B1):c.1216del (p.Arg406fs)	MAN1B1	Pathogenic	criteria provided, single submitter
4747916	NM_016219.5(MAN1B1):c.1014dup (p.Leu339fs)	MAN1B1	Pathogenic	criteria provided, single submitter
4772561	NM_016219.5(MAN1B1):c.1240dup (p.Asp414fs)	MAN1B1	Pathogenic	criteria provided, single submitter
521615	NM_016219.5(MAN1B1):c.1833_1834del (p.Asp613fs)	MAN1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
983290	NM_016219.5(MAN1B1):c.1225T>C (p.Ser409Pro)	MAN1B1	Pathogenic	no assertion criteria provided
983293	NM_016219.5(MAN1B1):c.1445+2_1445+5del	MAN1B1	Pathogenic	criteria provided, single submitter
983295	NM_016219.5(MAN1B1):c.621-2A>G	MAN1B1	Pathogenic	no assertion criteria provided
983297	NM_016219.5(MAN1B1):c.761_764del (p.Ile254fs)	MAN1B1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
MAN1B1	Definitive	Autosomal recessive	Rafiq syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAN1B1	Orphanet:397941	MAN1B1-CDG
MAN1B1	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
ABCA2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability

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
MAN1B1	HGNC:6823	ENSG00000177239	Q9UKM7	Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase	gencc,clinvar
VAV2	HGNC:12658	ENSG00000160293	P52735	Guanine nucleotide exchange factor VAV2	clinvar
ABCA2	HGNC:32	ENSG00000107331	Q9BZC7	ATP-binding cassette sub-family A member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAN1B1	Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase	Involved in glycoprotein quality control targeting of misfolded glycoproteins for degradation.
VAV2	Guanine nucleotide exchange factor VAV2	Guanine nucleotide exchange factor for the Rho family of Ras-related GTPases.
ABCA2	ATP-binding cassette sub-family A member 2	Probable lipid transporter that modulates cholesterol sequestration in the late endosome/lysosome by regulating the intracellular sphingolipid metabolism, in turn participates in cholesterol homeostasis.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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
Transporter	1	25.9×	0.114
Scaffold/PPI	1	5.8×	0.230
Enzyme (other)	1	4.0×	0.230

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MAN1B1	Enzyme (other)	yes	3.2.1.113	Glyco_hydro_47, 6hp_glycosidase-like_sf, Seven-hairpin_glycosidases
VAV2	Scaffold/PPI	no		DH_dom, SH2, GDS_CDC24_CS
ABCA2	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM

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
right uterine tube	1
skin of leg	1
stromal cell of endometrium	1
ganglionic eminence	1
parotid gland	1
ventricular zone	1
C1 segment of cervical spinal cord	1
right hemisphere of cerebellum	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAN1B1	268	ubiquitous	marker	stromal cell of endometrium, right uterine tube, skin of leg
VAV2	248	ubiquitous	marker	parotid gland, ganglionic eminence, ventricular zone
ABCA2	234	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VAV2	1,746
MAN1B1	1,682
ABCA2	1,678

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VAV2	P52735	7
MAN1B1	Q9UKM7	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABCA2	Q9BZC7	71.46

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
Defective MAN1B1 causes MRT15	1	3806.7×	0.011	MAN1B1
Calnexin/calreticulin cycle	1	237.9×	0.027	MAN1B1
Diseases associated with N-glycosylation of proteins	1	211.5×	0.027	MAN1B1
ABC transporters in lipid homeostasis	1	200.3×	0.027	ABCA2
ER Quality Control Compartment (ERQC)	1	181.3×	0.027	MAN1B1
Signal transduction by L1	1	173.0×	0.027	VAV2
Azathioprine ADME	1	165.5×	0.027	VAV2
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	165.5×	0.027	VAV2
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	141.0×	0.027	MAN1B1
VEGFR2 mediated vascular permeability	1	135.9×	0.027	VAV2
Translation of Structural Proteins	1	135.9×	0.027	MAN1B1
DAP12 signaling	1	122.8×	0.027	VAV2
FCERI mediated Ca+2 mobilization	1	119.0×	0.027	VAV2
FCERI mediated MAPK activation	1	115.3×	0.027	VAV2
GPVI-mediated activation cascade	1	102.9×	0.027	VAV2
Late SARS-CoV-2 Infection Events	1	97.6×	0.027	MAN1B1
Maturation of spike protein	1	88.5×	0.028	MAN1B1
EPH-ephrin mediated repulsion of cells	1	73.2×	0.032	VAV2
FCGR3A-mediated phagocytosis	1	62.4×	0.033	VAV2
NRAGE signals death through JNK	1	61.4×	0.033	VAV2
Regulation of actin dynamics for phagocytic cup formation	1	61.4×	0.033	VAV2
RHOB GTPase cycle	1	51.4×	0.036	VAV2
RHOG GTPase cycle	1	49.4×	0.036	VAV2
RHOC GTPase cycle	1	48.8×	0.036	VAV2
VEGFA-VEGFR2 Pathway	1	46.4×	0.036	VAV2
G alpha (12/13) signalling events	1	45.9×	0.036	VAV2
Diseases of glycosylation	1	43.8×	0.036	MAN1B1
RAC2 GTPase cycle	1	42.3×	0.036	VAV2
ABC-family protein mediated transport	1	40.5×	0.036	ABCA2
RAC3 GTPase cycle	1	39.6×	0.036	VAV2

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
negative regulation of intracellular cholesterol transport	1	5617.3×	0.002	ABCA2
protein alpha-1,2-demannosylation	1	5617.3×	0.002	MAN1B1
negative regulation of phospholipid biosynthetic process	1	5617.3×	0.002	ABCA2
negative regulation of sphingolipid biosynthetic process	1	5617.3×	0.002	ABCA2
regulation of protein localization to cell periphery	1	5617.3×	0.002	ABCA2
negative regulation of steroid metabolic process	1	2808.7×	0.002	ABCA2
ceramide translocation	1	2808.7×	0.002	ABCA2
regulation of post-translational protein modification	1	2808.7×	0.002	ABCA2
negative regulation of receptor-mediated endocytosis involved in cholesterol transport	1	2808.7×	0.002	ABCA2
positive regulation of low-density lipoprotein particle receptor catabolic process	1	1872.4×	0.003	ABCA2
ganglioside metabolic process	1	1404.3×	0.003	ABCA2
regulation of intracellular cholesterol transport	1	1404.3×	0.003	ABCA2
sphingomyelin metabolic process	1	1123.5×	0.003	ABCA2
positive regulation of amyloid precursor protein biosynthetic process	1	1123.5×	0.003	ABCA2
intracellular sphingolipid homeostasis	1	1123.5×	0.003	ABCA2
negative regulation of cholesterol efflux	1	936.2×	0.003	ABCA2
glycosphingolipid metabolic process	1	802.5×	0.003	ABCA2
regulation of steroid metabolic process	1	802.5×	0.003	ABCA2
central nervous system myelin formation	1	802.5×	0.003	ABCA2
immune response-regulating cell surface receptor signaling pathway	1	624.1×	0.004	VAV2
response to cholesterol	1	561.7×	0.004	ABCA2
positive regulation of amyloid precursor protein catabolic process	1	561.7×	0.004	ABCA2
regulation of protein localization to cell surface	1	561.7×	0.004	ABCA2
endoplasmic reticulum mannose trimming	1	401.2×	0.005	MAN1B1
sphingosine biosynthetic process	1	351.1×	0.006	ABCA2
positive regulation of amyloid-beta formation	1	295.6×	0.007	ABCA2
response to steroid hormone	1	280.9×	0.007	ABCA2
regulation of cell size	1	255.3×	0.007	VAV2
N-glycan processing	1	244.2×	0.007	MAN1B1
Fc-epsilon receptor signaling pathway	1	244.2×	0.007	VAV2

Therapeutics

Drug target analysis

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

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
MAN1B1	0	0
VAV2	0	0
ABCA2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MAN1B1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MAN1B1	3.2.1.113, 3.2.1.209	mannosyl-oligosaccharide 1,2-alpha-mannosidase, endoplasmic reticulum Man9GlcNAc2 1,2-alpha-mannosidase

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

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	1	MAN1B1
D	Druggable family + AlphaFold only, no drug	1	ABCA2
E	Difficult family or no structure, no drug	1	VAV2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MAN1B1	1	—
VAV2	0	—
ABCA2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.