RFX5

Summary

RFX5 (regulatory factor X5, HGNC:9986) is a protein-coding gene on chromosome 1q21.3, encoding DNA-binding protein RFX5 (P48382). Activates transcription from class II MHC promoters.

A lack of MHC-II expression results in a severe immunodeficiency syndrome called MHC-II deficiency, or the bare lymphocyte syndrome (BLS; MIM 209920). At least 4 complementation groups have been identified in B-cell lines established from patients with BLS. The molecular defects in complementation groups B, C, and D all lead to a deficiency in RFX, a nuclear protein complex that binds to the X box of MHC-II promoters. The lack of RFX binding activity in complementation group C results from mutations in the RFX5 gene encoding the 75-kD subunit of RFX (Steimle et al., 1995). RFX5 is the fifth member of the growing family of DNA-binding proteins sharing a novel and highly characteristic DNA-binding domain called the RFX motif. Multiple alternatively spliced transcript variants have been found but the full-length natures of only two have been determined.

Source: NCBI Gene 5993 — RefSeq curated summary.

At a glance

• Gene–disease (curated): MHC class II deficiency (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 470 total — 30 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 58
• Transcription factor: yes — 27 downstream targets (CollecTRI)
• MANE Select transcript: NM_001025603

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9986
Approved symbol	RFX5
Name	regulatory factor X5
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000143390
Ensembl biotype	protein_coding
OMIM	601863
Entrez	5993

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 23 protein_coding, 4 nonsense_mediated_decay, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000290524, ENST00000368870, ENST00000392746, ENST00000412774, ENST00000421986, ENST00000422595, ENST00000430227, ENST00000435314, ENST00000436271, ENST00000436637, ENST00000437327, ENST00000444392, ENST00000450506, ENST00000452456, ENST00000452671, ENST00000458484, ENST00000469513, ENST00000475144, ENST00000478564, ENST00000479681, ENST00000494217, ENST00000882446, ENST00000882447, ENST00000882448, ENST00000882449, ENST00000882450, ENST00000939315, ENST00000939316, ENST00000939317, ENST00000939318, ENST00000939319, ENST00000943235

RefSeq mRNA: 11 — MANE Select: NM_001025603 NM_000449, NM_001025603, NM_001379412, NM_001379413, NM_001379414, NM_001379415, NM_001379416, NM_001379417, NM_001379418, NM_001379419, NM_001379420

CCDS: CCDS994

Canonical transcript exons

ENST00000452671 — 11 exons

Exon	Start	End
ENSE00000959765	151344417	151344536
ENSE00000959767	151343681	151343882
ENSE00000959768	151343342	151343442
ENSE00001045122	151340640	151343178
ENSE00001448154	151346489	151346606
ENSE00001865079	151347211	151347252
ENSE00003532823	151346205	151346333
ENSE00003624294	151345928	151345961
ENSE00003647996	151345106	151345188
ENSE00003689514	151344197	151344278
ENSE00003785278	151344728	151344847

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 95.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.5053 / max 143.1300, expressed in 1759 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14434	8.3064	1732
14433	2.0412	842
14432	0.6177	308
14431	0.5329	264
14430	0.0070	3

Top tissues by expression

296 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
epithelium of nasopharynx	UBERON:0001951	95.55	gold quality
lymph node	UBERON:0000029	95.24	gold quality
monocyte	CL:0000576	94.85	gold quality
vermiform appendix	UBERON:0001154	94.81	gold quality
mononuclear cell	CL:0000842	94.71	gold quality
leukocyte	CL:0000738	94.45	gold quality
caecum	UBERON:0001153	94.10	gold quality
granulocyte	CL:0000094	93.45	gold quality
right adrenal gland cortex	UBERON:0035827	92.40	gold quality
rectum	UBERON:0001052	92.33	gold quality
tonsil	UBERON:0002372	91.97	gold quality
spleen	UBERON:0002106	91.89	gold quality
right adrenal gland	UBERON:0001233	91.77	gold quality
pons	UBERON:0000988	91.60	gold quality
smooth muscle tissue	UBERON:0001135	91.50	gold quality
gall bladder	UBERON:0002110	91.30	gold quality
palpebral conjunctiva	UBERON:0001812	91.11	gold quality
pylorus	UBERON:0001166	90.97	gold quality
adrenal cortex	UBERON:0001235	90.77	gold quality
tibia	UBERON:0000979	90.76	gold quality
left adrenal gland	UBERON:0001234	90.59	gold quality
left adrenal gland cortex	UBERON:0035825	90.54	gold quality
bone marrow cell	CL:0002092	90.48	gold quality
adrenal gland	UBERON:0002369	90.02	gold quality
eye	UBERON:0000970	89.73	gold quality
mucosa of stomach	UBERON:0001199	89.66	gold quality
cartilage tissue	UBERON:0002418	89.61	gold quality
cardia of stomach	UBERON:0001162	89.47	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.45	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.42	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ENAD-27	yes	59.57
E-ANND-3	yes	6.13

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

27 targets.

Target	Regulation
CD74	Unknown
CIITA
COL1A2	Repression
CR2
HDAC2	Unknown
HLA-DMA	Unknown
HLA-DMB	Unknown
HLA-DOA	Unknown
HLA-DOB	Unknown
HLA-DPA1	Unknown
HLA-DPB1	Unknown
HLA-DQA1	Unknown
HLA-DQA2	Unknown
HLA-DQB1	Unknown
HLA-DQB2	Unknown
HLA-DRA	Unknown
HLA-DRB1	Unknown
HLA-DRB3	Unknown
HLA-DRB4	Unknown
HLA-DRB5	Unknown
HLA-E	Unknown
HLA-F
HLA-G
IFNG	Unknown
RFX5
SIN3B
SIRT1

JASPAR motifs

Motif	Name	Family
MA0510.1	RFX5	RFX-related factors
MA0510.2	RFX5	RFX-related factors
MA0510.3	RFX5	RFX-related factors

JASPAR matrix evidence (PMIDs): PMID:8754849

Upstream regulators (CollecTRI, top): NFYB, RFX5

miRNA regulators (miRDB)

80 targeting RFX5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3658	99.96	73.87	4379
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-4499	99.62	67.29	1470

Literature-anchored findings (GeneRIF, showing 15)

• interaction at COL1A2 start site and transcription repression (PMID:11986307)
• The mutation for the fifth Bbare lymphocyte syndrome complementation group was found in RFX5 and was mapped to one of the arginines in a DNA-binding surface of this protein. Its wild-type counterpart restored function. (PMID:12368908)
• RFX5 binds to the collagen transcription start site and represses collagen gene expression (PMID:12968017)
• The identification of nuclear import and export sites on RFX molecules provides potential targets to modulate MHC class II expression. (PMID:15210800)
• results demonstrate that RFX1 and RFX5 differentially interact with class I HDACs underlying the different pathways when repressing collagen synthesis (PMID:16464847)
• PPARgamma is within the RFX5.CIITA complex as judged by co-immunoprecipitation and DNA affinity precipitation studies (PMID:17611194)
• RFXAP and RFXB have roles in relieving autoinhibition of RFX5 (PMID:18723135)
• TSA treatment enhances the association of CIITA with the transcription factor RFX5, which ameliorates the down-regulation of CIITA recruitment to target promoters by HDAC2. (PMID:19041327)
• RFXAP(C) consists of two alpha-helices that form a V-shaped structure that packs within the RFX5(N)(2) staple. (PMID:20732328)
• these data have identified as novel pathway whereby SIRT1 maintains COL1A2 synthesis in SMCs by modulating RFX5 activity. (PMID:23079621)
• Data show arginine methyltransferase PRMT6 methylates the AT-hook motif of regulatory factor RFX5 and downregulates HLA-DQ expression. (PMID:23911394)
• RFX5 acts as a direct positive transcriptional regulator of TPP1 in hepatocellular carcinoma. (PMID:27840983)
• RFX5 promotes the progression of hepatocellular carcinoma through transcriptional activation of KDM4A. (PMID:32883983)
• RFX5 regulates gene expression of the Pcdhalpha cluster. (PMID:32952112)
• Identification of RFX5 as prognostic biomarker and associated with immune infiltration in stomach adenocarcinoma. (PMID:36045400)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rfx5	ENSDARG00000063258
mus_musculus	Rfx5	ENSMUSG00000005774
rattus_norvegicus	Rfx5	ENSRNOG00000021012
drosophila_melanogaster	CG9727	FBGN0037445

Paralogs (7): RFX3 (ENSG00000080298), RFX2 (ENSG00000087903), RFX4 (ENSG00000111783), RFX1 (ENSG00000132005), RFX7 (ENSG00000181827), RFX6 (ENSG00000185002), RFX8 (ENSG00000196460)

Protein

Protein identifiers

DNA-binding protein RFX5 — P48382 (reviewed: P48382)

Alternative names: Regulatory factor X 5

All UniProt accessions (13): P48382, A0A0A0MSM9, A0A0A0MSQ2, A0A0A0MT34, F2Z2G0, F6R6G4, F6S3S0, F6UE82, F6X9D6, F8W689, F8WDU3, F8WFE4, H0Y4B4

UniProt curated annotations — full annotation on UniProt →

Function. Activates transcription from class II MHC promoters. Recognizes X-boxes. Mediates cooperative binding between RFX and NF-Y. RFX binds the X1 box of MHC-II promoters.

Subunit / interactions. Homodimer. The RFX heterotetrameric complex consists of 2 molecules of RFX5 and one each of RFXAP and RFX-B/RFXANK; with each subunit representing a separate complementation group. Interacts (via PxLPxI/L motif) with RFXANK (via ankyrin repeats); the interaction is direct. RFX forms cooperative DNA binding complexes with X2BP and CBF/NF-Y. RFX associates with CIITA to form an active transcriptional complex.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylated.

Disease relevance. MHC class II deficiency 3 (MHC2D3) [MIM:620816] An autosomal recessive disorder characterized by immunodeficiency and recurrent bacterial, viral, fungal and parasitic infections from birth, usually affecting the respiratory and gastrointestinal tract. Most patients die in infancy or early childhood. The disease is caused by variants affecting the gene represented in this entry. MHC class II deficiency 5 (MHC2D5) [MIM:620818] An autosomal recessive disorder characterized by a defect in constitutive and inducible surface expression of MHC class II molecules on B cells, monocytes, and activated T cells. Affected individuals may present in infancy with infections and hypogammaglobulinemia, but the disease course is mostly benign and patients do not develop severe infections. Some individuals may be asymptomatic. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminus is required for dimer formation, association with RFXANK and RFXAP, assembly of the RFX complex, and for binding of this complex to its X box target site in the MHC-II promoter. The C-terminus mediates cooperative binding between the RFX complex and NF-Y. The PxLPxI/L motif mediates interaction with ankyrin repeats of RFXANK.

Similarity. Belongs to the RFX family.

Isoforms (2)

UniProt ID	Names	Canonical?
P48382-1	1	yes
P48382-2	2

RefSeq proteins (11): NP_000440, NP_001020774, NP_001366341, NP_001366342, NP_001366343, NP_001366344, NP_001366345, NP_001366346, NP_001366347, NP_001366348, NP_001366349 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003150	DNA-bd_RFX	Domain
IPR029298	RFX5_C	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR039779	RFX-like	Family

Pfam: PF02257, PF14621, PF18326

UniProt features (33 total): compositionally biased region 7, sequence variant 7, region of interest 5, helix 4, modified residue 3, strand 2, initiator methionine 1, chain 1, splice variant 1, DNA-binding region 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3V30	X-RAY DIFFRACTION	1.57
8ZJR	ELECTRON MICROSCOPY	3.3
2KW3	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48382-F1	58.48	0.20

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 2, 10, 185

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 367 (showing top): CREL_01, CCAWYNNGAAR_UNKNOWN, MAZ_Q6, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, TGACCTY_ERR1_Q2, WIELAND_UP_BY_HBV_INFECTION, NFKB_Q6, PUJANA_CHEK2_PCC_NETWORK, IRF7_01, MYCMAX_01, GCM_DPF2, GNF2_FBL, E4F1_Q6, HIF1_Q3, ATF4_Q2

GO Biological Process (5): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of MHC class II biosynthetic process (GO:0045348), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (10): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coregulator binding (GO:0001221), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), RNA polymerase II transcription regulator complex (GO:0090575)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
positive regulation of macromolecule biosynthetic process	1
MHC class II biosynthetic process	1
regulation of MHC class II biosynthetic process	1
positive regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription factor binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription regulator activity	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
transcription regulator complex	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

978 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RFX5	RFXAP	O00287	999
RFX5	RFXANK	O14593	999
RFX5	CIITA	P33076	985
RFX5	CREB1	P16220	813
RFX5	NFYB	P25208	809
RFX5	USF1	P22415	753
RFX5	NFYA	P23511	749
RFX5	NFYC	Q13952	725
RFX5	HLA-DRA	P01903	715
RFX5	USF2	Q15853	670
RFX5	ANK1	P16157	645
RFX5	ANK2	Q01484	645
RFX5	ANK3	Q12955	643
RFX5	CBX3	Q13185	610
RFX5	RFX1	P22670	585

IntAct

51 interactions, top by confidence:

A	B	Type	Score
RFX5	RFXAP	psi-mi:“MI:0914”(association)	0.880
RFX5	RFXAP	psi-mi:“MI:0407”(direct interaction)	0.880
RFXAP	RFX5	psi-mi:“MI:0407”(direct interaction)	0.880
RFX5	RFXAP	psi-mi:“MI:0915”(physical association)	0.880
RFXANK	RFX5	psi-mi:“MI:0407”(direct interaction)	0.850
RFX5	RFXANK	psi-mi:“MI:0915”(physical association)	0.850
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
HDAC2	SIN3B	psi-mi:“MI:0914”(association)	0.640
RFX5	HLA-DRA	psi-mi:“MI:0407”(direct interaction)	0.560
HDAC2	RFX5	psi-mi:“MI:0915”(physical association)	0.500
U2SURP	SMNDC1	psi-mi:“MI:0914”(association)	0.480
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
CIITA	RFX5	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (74): RFX5 (Affinity Capture-RNA), RFX5 (Affinity Capture-RNA), PPARG (Affinity Capture-Western), RFX5 (Affinity Capture-Western), RFX5 (Reconstituted Complex), RFX5 (Affinity Capture-MS), RFX5 (Affinity Capture-MS), RFX5 (Proximity Label-MS), RFX5 (Proximity Label-MS), RFX5 (Proximity Label-MS), RFXAP (Affinity Capture-MS), GIGYF2 (Affinity Capture-MS), CDC73 (Affinity Capture-MS), RFX5 (Affinity Capture-Western), RFX7 (Affinity Capture-MS)

ESM2 similar proteins: A2VDR9, A5PKG8, A6NMT0, A7MB40, A8MUI8, E2R9X2, O00257, O15353, O43151, O55187, P19419, P30658, P48382, P52950, P59598, Q03989, Q0GGX2, Q13029, Q14781, Q28BT7, Q2MHN3, Q32MQ0, Q32N19, Q3SWY1, Q3TEI4, Q3U108, Q3UHR0, Q497V6, Q568E2, Q571I4, Q5JPB2, Q5NSW5, Q5TGY3, Q61818, Q6PAL7, Q6ZRI6, Q7TSH3, Q7Z5J4, Q811R2, Q86YN6

Diamond homologs: A0A1L8GWK2, A0A1L8H0H2, A0JMF8, A2BGA0, A6QLW9, B1WAV2, B2GV50, D2HNW6, F8VPJ6, P22670, P48377, P48378, P48379, P48380, P48381, P48382, P48743, Q09555, Q0V9K5, Q2KHR2, Q32NR3, Q33E94, Q4R3I8, Q4R3Z4, Q59V88, Q5EAP5, Q5RDR2, Q5RJA1, Q7TNK1, Q8C7R7, Q8HWS3, Q9JL61, D3YU81, P48383, Q6ZV50, Q5AMQ6

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
CIITA	“up-regulates activity”	RFX5	binding
IFNG	“up-regulates activity”	RFX5
RFX5	“up-regulates quantity by expression”	HLA-DRA	“transcriptional regulation”
RFX5	“form complex”	“RFX complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Dengue Virus-Host Interactions	6	14.4×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

470 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	16
Uncertain significance	247
Likely benign	130
Benign	9

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072890	NM_001025603.2(RFX5):c.273T>G (p.Tyr91Ter)	Pathogenic
1380120	NM_001025603.2(RFX5):c.602del (p.Val201fs)	Pathogenic
1414875	NM_001025603.2(RFX5):c.445C>T (p.Arg149Ter)	Pathogenic
1496062	NM_001025603.2(RFX5):c.1016C>G (p.Ser339Ter)	Pathogenic
1998869	NM_001025603.2(RFX5):c.1034_1035del (p.Pro345fs)	Pathogenic
2030092	NM_001025603.2(RFX5):c.151-1G>T	Pathogenic
2096008	NM_001025603.2(RFX5):c.55_56dup (p.Gly20fs)	Pathogenic
2114173	NM_001025603.2(RFX5):c.1374dup (p.Ala459fs)	Pathogenic
2151896	NM_001025603.2(RFX5):c.715C>T (p.Arg239Ter)	Pathogenic
2156804	NM_001025603.2(RFX5):c.367_368del (p.Leu124fs)	Pathogenic
2706050	NM_001025603.2(RFX5):c.809T>G (p.Leu270Ter)	Pathogenic
2733985	NM_001025603.2(RFX5):c.961C>T (p.Gln321Ter)	Pathogenic
2808991	NM_001025603.2(RFX5):c.172del (p.Asp58fs)	Pathogenic
2809942	NM_001025603.2(RFX5):c.582del (p.Ala195fs)	Pathogenic
2853561	NM_001025603.2(RFX5):c.1059del (p.Arg354fs)	Pathogenic
2854392	NM_001025603.2(RFX5):c.1008_1014del (p.Pro337fs)	Pathogenic
2981568	NM_001025603.2(RFX5):c.1408C>T (p.Arg470Ter)	Pathogenic
2995578	NM_001025603.2(RFX5):c.1499G>A (p.Trp500Ter)	Pathogenic
3236741	NM_001025603.2(RFX5):c.1239_1240del (p.Asn414fs)	Pathogenic
3660753	NM_001025603.2(RFX5):c.1222C>T (p.Gln408Ter)	Pathogenic
4697920	NM_001025603.2(RFX5):c.1414_1415del (p.Lys472fs)	Pathogenic
4734136	NM_001025603.2(RFX5):c.763del (p.Asp255fs)	Pathogenic
4744546	NM_001025603.2(RFX5):c.198dup (p.Gln67fs)	Pathogenic
4760775	NM_001025603.2(RFX5):c.56del (p.Pro19fs)	Pathogenic
648114	NM_001025603.2(RFX5):c.312dup (p.Asp105Ter)	Pathogenic
649396	NM_001025603.2(RFX5):c.609del (p.Ala204fs)	Pathogenic
7644	NM_001025603.2(RFX5):c.116+5G>A	Pathogenic
7646	NM_001025603.2(RFX5):c.234-1G>A	Pathogenic
7647	NM_001025603.2(RFX5):c.151-1G>A	Pathogenic
948575	NM_001025603.2(RFX5):c.1578_1594dup (p.Gln532fs)	Pathogenic

SpliceAI

1759 predictions. Top by Δscore:

Variant	Effect	Δscore
1:151343177:GG:G	acceptor_gain	1.0000
1:151343179:C:CC	acceptor_gain	1.0000
1:151343335:T:TA	donor_gain	1.0000
1:151343336:CCTTA:C	donor_loss	1.0000
1:151343337:CTTAC:C	donor_loss	1.0000
1:151343338:TTA:T	donor_loss	1.0000
1:151343340:A:AC	donor_gain	1.0000
1:151343341:C:CC	donor_gain	1.0000
1:151343341:C:CT	donor_loss	1.0000
1:151343438:CTCTT:C	acceptor_gain	1.0000
1:151343440:CTT:C	acceptor_gain	1.0000
1:151343441:TT:T	acceptor_gain	1.0000
1:151343442:TC:T	acceptor_loss	1.0000
1:151343443:C:CC	acceptor_gain	1.0000
1:151343443:C:T	acceptor_loss	1.0000
1:151343451:G:C	acceptor_gain	1.0000
1:151343451:G:GC	acceptor_gain	1.0000
1:151343455:C:CT	acceptor_gain	1.0000
1:151343455:C:T	acceptor_gain	1.0000
1:151343456:A:T	acceptor_gain	1.0000
1:151344418:TGG:T	donor_gain	1.0000
1:151344779:T:TA	donor_gain	1.0000
1:151344843:CTGAG:C	acceptor_gain	1.0000
1:151344844:TGAGC:T	acceptor_loss	1.0000
1:151344845:GAG:G	acceptor_gain	1.0000
1:151344846:AGC:A	acceptor_loss	1.0000
1:151344848:C:CC	acceptor_gain	1.0000
1:151344848:CTACA:C	acceptor_loss	1.0000
1:151345185:CTTG:C	acceptor_gain	1.0000
1:151345186:TTG:T	acceptor_gain	1.0000

AlphaMissense

3931 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:151344276:T:C	Y159C	1.000
1:151344277:A:G	Y159H	1.000
1:151344441:C:A	R150M	1.000
1:151344483:C:T	G136D	1.000
1:151344486:A:G	F135S	1.000
1:151344751:C:A	K110N	1.000
1:151344751:C:G	K110N	1.000
1:151344782:A:G	L100P	1.000
1:151344798:A:G	W95R	1.000
1:151344798:A:T	W95R	1.000
1:151343749:A:G	L230P	0.999
1:151343778:G:C	F220L	0.999
1:151343778:G:T	F220L	0.999
1:151343780:A:G	F220L	0.999
1:151343805:C:A	W211C	0.999
1:151343805:C:G	W211C	0.999
1:151343807:A:G	W211R	0.999
1:151343807:A:T	W211R	0.999
1:151343818:A:G	L207P	0.999
1:151344261:A:G	I164T	0.999
1:151344261:A:T	I164K	0.999
1:151344271:A:G	Y161H	0.999
1:151344440:C:A	R150S	0.999
1:151344440:C:G	R150S	0.999
1:151344441:C:G	R150T	0.999
1:151344442:T:C	R150G	0.999
1:151344444:C:G	R149P	0.999
1:151344447:G:T	A148D	0.999
1:151344461:G:C	F143L	0.999
1:151344461:G:T	F143L	0.999

dbSNP variants (sampled 300 via entrez): RS1000331736 (1:151345766 C>T), RS1000498631 (1:151340484 A>G), RS1000760098 (1:151340140 C>A), RS1000925865 (1:151347362 C>A,T), RS1001202328 (1:151346445 C>T), RS1001346581 (1:151348957 G>A,T), RS1001602081 (1:151346974 T>A), RS1002199720 (1:151348529 G>A,C), RS1002460916 (1:151340828 T>C), RS1003020201 (1:151347126 C>T), RS1004560498 (1:151343149 C>T), RS1004698893 (1:151345432 AC>A), RS1005540928 (1:151345380 C>A,G), RS1005966702 (1:151345054 C>A,T), RS1007005474 (1:151345694 G>T)

Disease associations

OMIM: gene MIM:601863 | disease phenotypes: MIM:209920, MIM:620816, MIM:620818

GenCC curated gene-disease

Disease	Classification	Inheritance
MHC class II deficiency	Definitive	Autosomal recessive
MHC class II deficiency 3	Strong	Autosomal recessive
MHC class II deficiency 5	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
MHC class II deficiency	Definitive	AR

Mondo (4): MHC class II deficiency (MONDO:0008855), MHC class II deficiency 1 (MONDO:0971005), MHC class II deficiency 3 (MONDO:0971014), MHC class II deficiency 5 (MONDO:0971016)

Orphanet (1): Immunodeficiency by defective expression of MHC class II (Orphanet:572)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000246	Sinusitis
HP:0000371	Acute otitis media
HP:0000403	Recurrent otitis media
HP:0000988	Skin rash
HP:0001260	Dysarthria
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001890	Autoimmune hemolytic anemia
HP:0001904	Autoimmune neutropenia
HP:0001973	Autoimmune thrombocytopenia
HP:0001999	Abnormal facial shape
HP:0002014	Diarrhea
HP:0002066	Gait ataxia
HP:0002090	Pneumonia
HP:0002110	Bronchiectasis
HP:0002205	Recurrent respiratory infections
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002718	Recurrent bacterial infections
HP:0002720	Decreased circulating IgA concentration
HP:0002726	Recurrent Staphylococcus aureus infections
HP:0002728	Chronic mucocutaneous candidiasis
HP:0002754	Osteomyelitis
HP:0002840	Lymphadenitis
HP:0002841	Recurrent fungal infections
HP:0002850	Decreased circulating total IgM
HP:0002960	Autoimmunity
HP:0003095	Septic arthritis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005951_38	Body mass index	4.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537079	Bare lymphocyte syndrome 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	5
Cyclosporine	decreases expression	3
Acetaminophen	decreases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
geraniol	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
methylparaben	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
hydroquinone	decreases expression	1
cadmium sulfate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	increases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1

Cellosaurus cell lines

18 cell lines: 11 transformed cell line, 4 cancer cell line, 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0T73	SJO	Transformed cell line	Female
CVCL_1886	RO	Transformed cell line	Male
CVCL_A5V6	SEES3-1V human RFX5, clone1	Embryonic stem cell	Male
CVCL_A5V7	SEES3-1V human RFX5, clone2	Embryonic stem cell	Male
CVCL_A5V8	SEES3-1V human RFX5, clone3	Embryonic stem cell	Male
CVCL_B3FZ	Abcam HEK293T RFX5 KO	Transformed cell line	Female
CVCL_B7LP	KER	Transformed cell line	Male
CVCL_B7M4	FSI	Transformed cell line	Male
CVCL_B7M5	WSI	Transformed cell line	Female
CVCL_B7M6	SSI	Transformed cell line

Clinical trials (associated diseases)

3 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT04251325	Not specified	UNKNOWN	Socio-demographic Characteristics of Basic Life Support Course Participants
NCT04353089	Not specified	UNKNOWN	Geographical Association Between Basic Life Support Courses, Bystander Cardiopulmonary Resuscitation and Survival