MHC class II deficiency 1

Summary

MHC class II deficiency 1 (MONDO:0971005) is a disease with 6 cohort genes.

At a glance

• Cohort genes: 6
• ClinVar variants: 44

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	MHC class II deficiency 1
Mondo ID	MONDO:0971005
OMIM	209920
GARD	0027099
Is cancer (heuristic)	no

Data availability: 44 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency › familial severe combined immunodeficiency › MHC class II deficiency › MHC class II deficiency 1

Related subtypes (4): MHC class II deficiency 2, MHC class II deficiency 3, MHC class II deficiency 4, MHC class II deficiency 5

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

44 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 11 likely pathogenic, 7 pathogenic/likely pathogenic, 7 pathogenic, 4 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076559	NM_000246.4(CIITA):c.632del (p.Pro211fs)	CIITA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1497267	NM_000246.4(CIITA):c.2889-1G>T	CIITA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236733	NM_000246.4(CIITA):c.929del (p.Asn310fs)	CIITA	Pathogenic	no assertion criteria provided
420718	NM_000246.4(CIITA):c.2290del (p.Gln764fs)	CIITA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
501277	NM_000246.4(CIITA):c.2888+1G>A	CIITA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
663446	NM_000246.4(CIITA):c.1962dup (p.Gly655fs)	CIITA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
664532	NM_000246.4(CIITA):c.922C>T (p.Arg308Ter)	CIITA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9541	NM_000246.4(CIITA):c.1141G>T (p.Glu381Ter)	CIITA	Pathogenic	no assertion criteria provided
9543	NM_000246.4(CIITA):c.2063G>A (p.Trp688Ter)	CIITA	Pathogenic	criteria provided, multiple submitters, no conflicts
9544	NM_000246.4(CIITA):c.2890_2969+1del	CIITA	Pathogenic	no assertion criteria provided
9545	NM_000246.4(CIITA):c.3080_3082del (p.Ile1027del)	CIITA	Pathogenic	no assertion criteria provided
1435455	NM_003721.4(RFXANK):c.338-25_338del	RFXANK	Pathogenic	criteria provided, multiple submitters, no conflicts
6600	NM_003721.4(RFXANK):c.362A>T (p.Asp121Val)	RFXANK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7651	NM_000538.4(RFXAP):c.368del (p.Ser123fs)	RFXAP	Pathogenic	criteria provided, multiple submitters, no conflicts
1496695	NM_000246.4(CIITA):c.199+1G>A	CIITA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2690567	NM_000246.4(CIITA):c.2698C>T (p.Gln900Ter)	CIITA	Likely pathogenic	criteria provided, single submitter
3362582	NM_000246.4(CIITA):c.1415_1421del (p.Leu472fs)	CIITA	Likely pathogenic	criteria provided, single submitter
3578232	NM_000246.4(CIITA):c.492del (p.Thr165fs)	CIITA	Likely pathogenic	criteria provided, single submitter
3578233	NM_000246.4(CIITA):c.628+1G>A	CIITA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3578234	NM_000246.4(CIITA):c.2382_2439delinsTGTATTCAGGTACCCAA (p.Lys794fs)	CIITA	Likely pathogenic	criteria provided, single submitter
4277775	NM_000246.4(CIITA):c.1335C>A (p.Tyr445Ter)	CIITA	Likely pathogenic	criteria provided, single submitter
666964	NM_000246.4(CIITA):c.338dup (p.Leu114fs)	CIITA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
9542	NM_000246.4(CIITA):c.3317+1G>A	CIITA	Likely pathogenic	criteria provided, single submitter
4820157	NM_000538.4(RFXAP):c.28_34dup (p.Pro12fs)	LOC130009573	Likely pathogenic	criteria provided, single submitter
3362569	NM_003721.4(RFXANK):c.8_11del (p.Leu3fs)	RFXANK	Likely pathogenic	criteria provided, single submitter
317716	NM_000246.4(CIITA):c.2651G>A (p.Arg884His)	CIITA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625921	NM_000246.4(CIITA):c.931A>G (p.Met311Val)	CIITA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
827997	NM_000246.4(CIITA):c.2817-8C>G	CIITA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
709357	NM_001025603.2(RFX5):c.233+4G>C	RFX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4086205	NM_003748.4(ALDH4A1):c.1262G>A (p.Cys421Tyr)	ALDH4A1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIBF1	Orphanet:475	Isolated Joubert syndrome
ALDH4A1	Orphanet:79101	Hyperprolinemia type 2
CIITA	Orphanet:572	Immunodeficiency by defective expression of MHC class II
RFX5	Orphanet:572	Immunodeficiency by defective expression of MHC class II
RFXANK	Orphanet:572	Immunodeficiency by defective expression of MHC class II
RFXAP	Orphanet:572	Immunodeficiency by defective expression of MHC class II

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIBF1	HGNC:23352	ENSG00000083535	Q8WXW3	Progesterone-induced-blocking factor 1	clinvar
ALDH4A1	HGNC:406	ENSG00000159423	P30038	Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial	clinvar
CIITA	HGNC:7067	ENSG00000179583	P33076	MHC class II transactivator	clinvar
RFX5	HGNC:9986	ENSG00000143390	P48382	DNA-binding protein RFX5	clinvar
RFXANK	HGNC:9987	ENSG00000064490	O14593	DNA-binding protein RFXANK	clinvar
RFXAP	HGNC:9988	ENSG00000133111	O00287	Regulatory factor X-associated protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIBF1	Progesterone-induced-blocking factor 1	Plays a role in ciliogenesis.
ALDH4A1	Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial	Irreversible conversion of delta-1-pyrroline-5-carboxylate (P5C), derived either from proline or ornithine, to glutamate.
CIITA	MHC class II transactivator	Essential for transcriptional activity of the HLA class II promoter; activation is via the proximal promoter.
RFX5	DNA-binding protein RFX5	Activates transcription from class II MHC promoters.
RFXANK	DNA-binding protein RFXANK	Activates transcription from class II MHC promoters.
RFXAP	Regulatory factor X-associated protein	Part of the RFX complex that binds to the X-box of MHC II promoters.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.17

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
Scaffold/PPI	1	2.9×	0.458
Enzyme (other)	1	2.0×	0.458
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIBF1	Other/Unknown	no		PIBF1
ALDH4A1	Enzyme (other)	yes	1.2.1.88	P5CDH/ALDH4A1, Aldehyde_DH_dom, Ald_DH_CS_CYS
CIITA	Other/Unknown	no		Leu-rich_rpt, NACHT_NTPase, MHC_II_transact
RFX5	Other/Unknown	no		DNA-bd_RFX, RFX5_C, WH-like_DNA-bd_sf
RFXANK	Scaffold/PPI	no		Ankyrin_rpt, DNA-bd_RFXANK, Ankyrin_rpt-contain_sf
RFXAP	Other/Unknown	no		RFXAP_RFXANK-bd, RFXAP_C_sf

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	2
calcaneal tendon	1
sural nerve	1
ventricular zone	1
adult mammalian kidney	1
liver	1
right lobe of liver	1
granulocyte	1
mononuclear cell	1
epithelium of nasopharynx	1
lymph node	1
lower esophagus mucosa	1
mucosa of transverse colon	1
right uterine tube	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIBF1	273	ubiquitous	marker	calcaneal tendon, ventricular zone, sural nerve
ALDH4A1	248	ubiquitous	marker	right lobe of liver, liver, adult mammalian kidney
CIITA	200	broad	marker	monocyte, granulocyte, mononuclear cell
RFX5	289	ubiquitous	marker	epithelium of nasopharynx, lymph node, monocyte
RFXANK	270	ubiquitous	marker	lower esophagus mucosa, mucosa of transverse colon, right uterine tube
RFXAP	231	ubiquitous	yes	primordial germ cell in gonad, tendon of biceps brachii, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH4A1	3,623
CIITA	2,388
RFXANK	1,957
PIBF1	1,706
RFX5	1,103
RFXAP	539

Intra-cohort edges

A	B	Sources
CIITA	RFX5	biogrid_interaction, intact, string_interaction
CIITA	RFXANK	biogrid_interaction, string_interaction
CIITA	RFXAP	string_interaction
RFX5	RFXANK	biogrid_interaction, intact, string_interaction
RFX5	RFXAP	biogrid_interaction, intact, string_interaction
RFXANK	RFXAP	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH4A1	P30038	6
RFX5	P48382	3
RFXANK	O14593	3
RFXAP	O00287	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIBF1	Q8WXW3	77.70
CIITA	P33076	69.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 6 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Proline catabolism	1	1903.3×	0.004	ALDH4A1
Glyoxylate metabolism and glycine degradation	1	380.7×	0.011	ALDH4A1
Interferon gamma signaling	1	62.8×	0.033	CIITA
Interferon Signaling	1	60.1×	0.033	CIITA
Metabolism of amino acids and derivatives	1	33.8×	0.047	ALDH4A1
Cytokine Signaling in Immune system	1	20.4×	0.065	CIITA
Immune System	1	6.5×	0.165	CIITA
Metabolism	1	5.8×	0.165	ALDH4A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of MHC class II biosynthetic process	4	802.5×	1e-10	CIITA, RFX5, RFXANK, RFXAP
positive regulation of transcription by RNA polymerase II	4	9.9×	0.004	CIITA, RFX5, RFXANK, RFXAP
negative regulation of prostaglandin biosynthetic process	1	1404.3×	0.005	PIBF1
L-proline metabolic process	1	936.2×	0.005	ALDH4A1
obsolete L-proline catabolic process to L-glutamate	1	936.2×	0.005	ALDH4A1
negative regulation of tyrosine phosphorylation of STAT protein	1	936.2×	0.005	PIBF1
L-proline catabolic process	1	702.2×	0.005	ALDH4A1
activation of Janus kinase activity	1	702.2×	0.005	PIBF1
trans-4-hydroxy-L-proline catabolic process	1	561.7×	0.006	ALDH4A1
positive regulation of MHC class I biosynthetic process	1	468.1×	0.006	CIITA
negative regulation of natural killer cell activation	1	351.1×	0.008	PIBF1
type II interferon-mediated signaling pathway	1	200.6×	0.012	CIITA
negative regulation of collagen biosynthetic process	1	187.2×	0.012	CIITA
negative regulation of interleukin-12 production	1	175.5×	0.012	PIBF1
positive regulation of tyrosine phosphorylation of STAT protein	1	122.1×	0.014	PIBF1
host-mediated suppression of symbiont invasion	1	117.0×	0.014	CIITA
response to antibiotic	1	117.0×	0.014	CIITA
protein localization to centrosome	1	112.3×	0.014	PIBF1
response to type II interferon	1	87.8×	0.017	CIITA
positive regulation of interleukin-10 production	1	66.9×	0.021	PIBF1
immune system process	1	65.3×	0.021	PIBF1
mitotic metaphase chromosome alignment	1	63.8×	0.021	PIBF1
mitotic spindle assembly	1	57.3×	0.022	PIBF1
non-motile cilium assembly	1	48.4×	0.025	PIBF1
Ras protein signal transduction	1	34.2×	0.033	RFXANK
negative regulation of transcription by RNA polymerase II	2	5.9×	0.046	CIITA, RFX5
cilium assembly	1	12.3×	0.085	PIBF1
regulation of transcription by RNA polymerase II	2	3.9×	0.091	RFX5, RFXAP
immune response	1	7.8×	0.121	CIITA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 1 of 6 evidence-associated genes (17%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIBF1	0	0
ALDH4A1	0	0
CIITA	0	0
RFX5	0	0
RFXANK	0	0
RFXAP	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
ALDH4A1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH4A1	1.2.1.88	L-glutamate gamma-semialdehyde dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	ALDH4A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	PIBF1, CIITA, RFX5, RFXANK, RFXAP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PIBF1	0	—
ALDH4A1	1	—
CIITA	0	—
RFX5	0	—
RFXANK	0	—
RFXAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.