RFX6

Summary

RFX6 (regulatory factor X6, HGNC:21478) is a protein-coding gene on chromosome 6q22.1, encoding DNA-binding protein RFX6 (Q8HWS3). Transcription factor required to direct islet cell differentiation during endocrine pancreas development.

The nuclear protein encoded by this gene is a member of the regulatory factor X (RFX) family of transcription factors. Studies in mice suggest that this gene is specifically required for the differentiation of islet cells for the production of insulin, but not for the differentiation of pancreatic polypeptide-producing cells. It regulates the transcription factors involved in beta-cell maturation and function, thus, restricting the expression of the beta-cell differentiation and specification genes. Mutations in this gene are associated with Mitchell-Riley syndrome, which is characterized by neonatal diabetes with pancreatic hypoplasia, duodenal and jejunal atresia, and gall bladder agenesis.

Source: NCBI Gene 222546 — RefSeq curated summary.

At a glance

• Gene–disease (curated): monogenic diabetes (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 318 total — 22 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 20
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_173560

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21478
Approved symbol	RFX6
Name	regulatory factor X6
Location	6q22.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC33442, dJ955L16.1
Ensembl gene	ENSG00000185002
Ensembl biotype	protein_coding
OMIM	612659
Entrez	222546

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 1 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000332958, ENST00000471966, ENST00000487683

RefSeq mRNA: 1 — MANE Select: NM_173560 NM_173560

CCDS: CCDS5113

Canonical transcript exons

ENST00000332958 — 19 exons

Exon	Start	End
ENSE00001294507	116925453	116925659
ENSE00001297740	116928759	116928971
ENSE00001305466	116923107	116923224
ENSE00001315557	116924669	116924791
ENSE00001316589	116931331	116932161
ENSE00001326895	116927027	116927539
ENSE00001907833	116877242	116877498
ENSE00003496953	116916008	116916085
ENSE00003502299	116920310	116920454
ENSE00003524883	116893987	116894064
ENSE00003534861	116895180	116895207
ENSE00003541218	116880544	116880667
ENSE00003550539	116919137	116919296
ENSE00003588998	116910935	116911042
ENSE00003613709	116918037	116918086
ENSE00003638040	116877796	116877952
ENSE00003676986	116922042	116922151
ENSE00003683615	116916201	116916314
ENSE00003689804	116882367	116882428

Expression profiles

Bgee: expression breadth broad, 55 present calls, max score 93.11.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2541 / max 203.6096, expressed in 36 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69443	0.2260	31
69442	0.0179	7
69444	0.0102	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	93.11	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.13	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.58	gold quality
pancreas	UBERON:0001264	72.62	gold quality
adrenal tissue	UBERON:0018303	67.97	gold quality
duodenum	UBERON:0002114	64.59	gold quality
rectum	UBERON:0001052	64.48	gold quality
body of pancreas	UBERON:0001150	63.76	gold quality
jejunal mucosa	UBERON:0000399	63.55	gold quality
pylorus	UBERON:0001166	60.31	gold quality
body of stomach	UBERON:0001161	57.89	gold quality
stomach	UBERON:0000945	57.50	gold quality
mucosa of sigmoid colon	UBERON:0004993	55.87	gold quality
placenta	UBERON:0001987	55.43	gold quality
jejunum	UBERON:0002115	53.03	gold quality
fundus of stomach	UBERON:0001160	51.77	gold quality
colonic mucosa	UBERON:0000317	51.68	silver quality
right adrenal gland	UBERON:0001233	49.52	gold quality
small intestine	UBERON:0002108	49.19	gold quality
adrenal gland	UBERON:0002369	48.14	gold quality
small intestine Peyer’s patch	UBERON:0003454	47.23	gold quality
mucosa of transverse colon	UBERON:0004991	47.19	gold quality
sural nerve	UBERON:0015488	47.14	gold quality
colonic epithelium	UBERON:0000397	45.57	gold quality
left adrenal gland cortex	UBERON:0035825	45.12	gold quality
transverse colon	UBERON:0001157	45.06	gold quality
right adrenal gland cortex	UBERON:0035827	44.78	gold quality
adrenal cortex	UBERON:0001235	44.69	gold quality
left adrenal gland	UBERON:0001234	44.16	gold quality
Brodmann (1909) area 23	UBERON:0013554	43.45	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	380.84
E-MTAB-5061	yes	28.03
E-GEOD-83139	yes	11.59
E-ENAD-27	no	7.59
E-ANND-3	no	5.68

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
GIP

Upstream regulators (CollecTRI, top): HOXB13

miRNA regulators (miRDB)

58 targeting RFX6, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-9-5P	100.00	72.28	2361
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-548AN	99.97	70.91	2817
HSA-MIR-507	99.97	70.11	1915
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-3609	99.52	69.89	2587

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 19)

• RFX6 is a winged helix transcription factor expressed almost exclusively in the pancreatic islets. (PMID:18673564)
• studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans (PMID:20148032)
• In early development Rfx6 plays a broad role, being essential for development of most anterior endodermal organs. At later stages however, Rfx6 function is restricted to endocrine cells. (PMID:21215266)
• Therefore, RFX6 appears to have a pivotal role in the maintenance of the phenotype of the beta-cells in addition to their development. (PMID:21750414)
• RFX6 mutation is responsible for neonatal diabetes syndrome. (PMID:21965172)
• Our results provide further support for association of the C2orf43, FOXP4, GPRC6A and RFX6 genes with prostate cancer in Eastern Asian populations (PMID:22662242)
• rs339331 in the RFX6 gene may be associated with prostate cancer as a susceptibility locus. (PMID:23803082)
• A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. (PMID:24390282)
• RFX6 controls insulin gene transcription, insulin content, and secretion by regulation of Ca(2+)-channel genes. (PMID:25497100)
• study reports two individuals each with compound heterozygous RFX6 nonsense mutations and an intestinal phenotype consistent with Mitchell-Riley syndrome, but with onset of diabetes in childhood rather than in the first 2 weeks of life (PMID:26264437)
• association of the THADA, FOXP4, GPRC6A/RFX6 and 8q24 genes with prostate cancer in Asian populations. (PMID:26537068)
• RFX6 heterozygous protein truncating variants cause reduced penetrance maturity-onset diabetes of the young (MODY). (PMID:29026101)
• Mitchell-Riley syndrome iPSCs exhibit reduced pancreatic endoderm differentiation due to a mutation in RFX6. (PMID:33033118)
• A novel RFX6 heterozygous mutation (p.R652X) in maturity-onset diabetes mellitus: A case report. (PMID:33721395)
• RFX6 Maintains Gene Expression and Function of Adult Human Islet alpha-Cells. (PMID:38064570)
• RFX6 facilitates aerobic glycolysis-mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1. (PMID:38093528)
• RFX6 regulates human intestinal patterning and function upstream of PDX1. (PMID:38587174)
• RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function. (PMID:38743124)
• An Inherited Allele Confers Prostate Cancer Progression and Drug Resistance via RFX6/HOXA10-Orchestrated TGFbeta Signaling. (PMID:38932472)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rfx6	ENSDARG00000041702
mus_musculus	Rfx6	ENSMUSG00000019900
rattus_norvegicus	Rfx6	ENSRNOG00000027949
caenorhabditis_elegans		WBGENE00000914

Paralogs (7): RFX3 (ENSG00000080298), RFX2 (ENSG00000087903), RFX4 (ENSG00000111783), RFX1 (ENSG00000132005), RFX5 (ENSG00000143390), RFX7 (ENSG00000181827), RFX8 (ENSG00000196460)

Protein

Protein identifiers

DNA-binding protein RFX6 — Q8HWS3 (reviewed: Q8HWS3)

Alternative names: Regulatory factor X 6, Regulatory factor X domain-containing protein 1

All UniProt accessions (1): Q8HWS3

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor required to direct islet cell differentiation during endocrine pancreas development. Specifically required for the differentiation of 4 of the 5 islet cell types and for the production of insulin. Not required for pancreatic PP (polypeptide-producing) cells differentiation. Acts downstream of NEUROG3 and regulates the transcription factors involved in beta-cell maturation and function, thereby restricting the expression of the beta-cell differentiation and specification genes, and thus the beta-cell fate choice. Activates transcription by forming a heterodimer with RFX3 and binding to the X-box in the promoter of target genes. Involved in glucose-stimulated insulin secretion by promoting insulin and L-type calcium channel gene transcription.

Subunit / interactions. Interacts with RFX3.

Subcellular location. Nucleus.

Tissue specificity. Expressed in pancreas. Expressed in pancreatic beta-cells (insulin-positive cells) and alpha-cells (glucagon-positive cells) (at protein level). Specifically expressed in pancreas, small intestine and colon. Expressed in endocrine cells in the islets.

Disease relevance. Mitchell-Riley syndrome (MTCHRS) [MIM:615710] A disorder characterized by neonatal diabetes, hypoplastic or annular pancreas, duodenal and jejunal atresia, and absent gallbladder. There is no dysmorphic features. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the RFX family.

RefSeq proteins (1): NP_775831* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003150	DNA-bd_RFX	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR039779	RFX-like	Family
IPR057321	RFX1-4/6/8-like_BCD	Domain

Pfam: PF02257, PF25340

UniProt features (11 total): sequence variant 7, region of interest 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8HWS3-F1	59.23	0.27

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-210745	Regulation of gene expression in beta cells

MSigDB gene sets: 173 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_INSULIN_SECRETION, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_NEUROGENESIS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELL_CELL_SIGNALING, GOBP_PANCREAS_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_INSULIN_SECRETION, GOBP_REGULATION_OF_PROTEIN_SECRETION, GOBP_ENDOCRINE_PANCREAS_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION

GO Biological Process (13): type B pancreatic cell differentiation (GO:0003309), pancreatic A cell differentiation (GO:0003310), pancreatic D cell differentiation (GO:0003311), regulation of transcription by RNA polymerase II (GO:0006357), endocrine pancreas development (GO:0031018), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), glucose homeostasis (GO:0042593), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of insulin secretion (GO:0050796), pancreatic epsilon cell differentiation (GO:0090104), regulation of DNA-templated transcription (GO:0006355), cell differentiation (GO:0030154)

GO Molecular Function (8): transcription cis-regulatory region binding (GO:0000976), 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), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Regulation of beta-cell development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endocrine pancreas development	4
enteroendocrine cell differentiation	3
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
intestinal type D enteroendocrine cell differentiation	1
pancreas development	1
endocrine system development	1
anatomical structure development	1
positive regulation of insulin secretion	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
carbohydrate homeostasis	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
insulin secretion	1
regulation of protein secretion	1
regulation of peptide hormone secretion	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cellular developmental process	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	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
nucleic acid binding	1
transcription regulator activity	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

798 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RFX6	NEUROG3	Q9Y4Z2	892
RFX6	DTX2	Q86UW9	865
RFX6	SS18L1	O75177	826
RFX6	CCNK	O75909	808
RFX6	NKX6-1	P78426	791
RFX6	MNX1	P50219	753
RFX6	NKX6-2	Q9C056	753
RFX6	GCK	P35557	737
RFX6	PLAGL1	Q9UM63	727
RFX6	NEUROD1	Q13562	725
RFX6	PTF1A	Q7RTS3	724
RFX6	PAX4	O43316	720
RFX6	PDX1	P52945	714
RFX6	ONECUT1	Q9UBC0	707
RFX6	PPY	P01298	707

IntAct

123 interactions, top by confidence:

A	B	Type	Score
FRS3	RFX6	psi-mi:“MI:0915”(physical association)	0.720
RFX6	SNRPB	psi-mi:“MI:0915”(physical association)	0.720
RFX6	CATSPER1	psi-mi:“MI:0915”(physical association)	0.720
RFX6	FRS3	psi-mi:“MI:0915”(physical association)	0.720
SNRPB	RFX6	psi-mi:“MI:0915”(physical association)	0.720
DTX2	RFX6	psi-mi:“MI:0915”(physical association)	0.670
RFX6	DTX2	psi-mi:“MI:0915”(physical association)	0.670
RFX2	RFX6	psi-mi:“MI:0915”(physical association)	0.670
RFX6	VPS37C	psi-mi:“MI:0915”(physical association)	0.560
RFX6	STK16	psi-mi:“MI:0915”(physical association)	0.560
PRKAA2	RFX6	psi-mi:“MI:0915”(physical association)	0.560
TLE5	RFX6	psi-mi:“MI:0915”(physical association)	0.560
PRKAA1	RFX6	psi-mi:“MI:0915”(physical association)	0.560
RFX6	NEDD9	psi-mi:“MI:0915”(physical association)	0.560
PLEKHN1	RFX6	psi-mi:“MI:0915”(physical association)	0.560
SNRPC	RFX6	psi-mi:“MI:0915”(physical association)	0.560
VPS37C	RFX6	psi-mi:“MI:0915”(physical association)	0.560
STK16	RFX6	psi-mi:“MI:0915”(physical association)	0.560
RFX6	TLE5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (51): RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid), RFX6 (Two-hybrid)

ESM2 similar proteins: A0A0G2JTY4, A2VD01, A5PMU4, A8E4V2, D2HNW6, E1BEQ5, O54972, O95644, P16236, P59281, P70365, P97305, Q12968, Q13191, Q13469, Q13905, Q15788, Q1LY51, Q2VPU4, Q3LRZ1, Q3TTA7, Q3U182, Q4PJW2, Q4VCS5, Q60591, Q61122, Q66IV1, Q68FF7, Q6DFR2, Q6GQL0, Q6NYU6, Q6ZNC4, Q80TM6, Q80VG1, Q8HWS3, Q8IXK0, Q8IY63, Q8K4S7, Q8N228, Q8VHG2

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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 42 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.

GO biological processes:

GO term	Partners	Fold	FDR
flagellated sperm motility	5	14.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	11
Uncertain significance	122
Likely benign	99
Benign	48

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2055284	NM_173560.4(RFX6):c.1037_1038del (p.Ile346fs)	Pathogenic
2134819	NM_173560.4(RFX6):c.2499del (p.Tyr834fs)	Pathogenic
223240	NM_173560.4(RFX6):c.2176C>T (p.Arg726Ter)	Pathogenic
2431227	NM_173560.4(RFX6):c.1555+1G>A	Pathogenic
2578066	NM_173560.4(RFX6):c.872T>A (p.Leu291Ter)	Pathogenic
2734002	NM_173560.4(RFX6):c.886C>T (p.Gln296Ter)	Pathogenic
3648833	NM_173560.4(RFX6):c.1652T>G (p.Leu551Ter)	Pathogenic
3654949	NM_173560.4(RFX6):c.609T>G (p.Tyr203Ter)	Pathogenic
3655181	NM_173560.4(RFX6):c.245del (p.Asn82fs)	Pathogenic
3685863	NM_173560.4(RFX6):c.2156del (p.Pro719fs)	Pathogenic
3720712	NM_173560.4(RFX6):c.1954C>T (p.Arg652Ter)	Pathogenic
4704182	NM_173560.4(RFX6):c.1513C>T (p.Arg505Ter)	Pathogenic
4726793	NM_173560.4(RFX6):c.1519del (p.Met507fs)	Pathogenic
4728673	NM_173560.4(RFX6):c.1465A>T (p.Lys489Ter)	Pathogenic
4735174	NM_173560.4(RFX6):c.842dup (p.Asn281fs)	Pathogenic
4744824	NM_173560.4(RFX6):c.2037del (p.Thr680fs)	Pathogenic
4779988	NM_173560.4(RFX6):c.1573C>T (p.Arg525Ter)	Pathogenic
496	NM_173560.4(RFX6):c.380+2T>C	Pathogenic
497	NM_173560.4(RFX6):c.224-12A>G	Pathogenic
498	NM_173560.4(RFX6):c.672+2T>G	Pathogenic
501	NM_173560.4(RFX6):c.779_780+12del	Pathogenic
587396	NM_173560.4(RFX6):c.1316_1319del (p.Ile439fs)	Pathogenic
1031716	NM_173560.4(RFX6):c.2290dup (p.Gln764fs)	Likely pathogenic
2631488	NM_173560.4(RFX6):c.781-1G>A	Likely pathogenic
2635430	NM_173560.4(RFX6):c.1278_1281del (p.Leu427fs)	Likely pathogenic
3032504	NM_173560.4(RFX6):c.1568T>A (p.Leu523Ter)	Likely pathogenic
3780548	NM_173560.4(RFX6):c.2034dup (p.Ser679fs)	Likely pathogenic
3899655	NM_173560.4(RFX6):c.872dup (p.Leu291fs)	Likely pathogenic
4082506	NM_173560.4(RFX6):c.619del (p.Val207fs)	Likely pathogenic
499	NM_173560.4(RFX6):c.649T>C (p.Ser217Pro)	Likely pathogenic

SpliceAI

2575 predictions. Top by Δscore:

Variant	Effect	Δscore
6:116877495:TCAG:T	donor_gain	1.0000
6:116877495:TCAGG:T	donor_loss	1.0000
6:116877496:CAGG:C	donor_loss	1.0000
6:116877498:GGTG:G	donor_loss	1.0000
6:116877499:G:GG	donor_gain	1.0000
6:116877783:A:AG	acceptor_gain	1.0000
6:116880664:AAAG:A	donor_loss	1.0000
6:116880665:AAGGT:A	donor_loss	1.0000
6:116880666:AG:A	donor_loss	1.0000
6:116880667:GG:G	donor_loss	1.0000
6:116880668:G:GC	donor_loss	1.0000
6:116880669:T:G	donor_loss	1.0000
6:116882429:G:GG	donor_gain	1.0000
6:116897023:A:T	donor_gain	1.0000
6:116916005:TA:T	acceptor_loss	1.0000
6:116916006:A:AG	acceptor_gain	1.0000
6:116916006:A:C	acceptor_loss	1.0000
6:116916007:G:GG	acceptor_gain	1.0000
6:116916083:GAG:G	donor_gain	1.0000
6:116916084:AGGT:A	donor_loss	1.0000
6:116916085:GGTAA:G	donor_loss	1.0000
6:116916086:G:C	donor_loss	1.0000
6:116916087:T:A	donor_loss	1.0000
6:116923178:TGCTC:T	donor_gain	1.0000
6:116923179:GCTCG:G	donor_gain	1.0000
6:116924626:A:AG	acceptor_gain	1.0000
6:116924627:C:G	acceptor_gain	1.0000
6:116924628:A:AG	acceptor_gain	1.0000
6:116924629:T:G	acceptor_gain	1.0000
6:116924633:A:AG	acceptor_gain	1.0000

AlphaMissense

6107 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:116877951:T:A	W127R	1.000
6:116877951:T:C	W127R	1.000
6:116880544:G:C	W127C	1.000
6:116880544:G:T	W127C	1.000
6:116880546:T:A	L128H	1.000
6:116880546:T:C	L128P	1.000
6:116880578:T:C	C139R	1.000
6:116880579:G:A	C139Y	1.000
6:116880580:C:G	C139W	1.000
6:116880582:T:C	L140S	1.000
6:116880587:C:G	R142G	1.000
6:116880587:C:T	R142W	1.000
6:116880597:T:A	L145H	1.000
6:116880597:T:C	L145P	1.000
6:116880608:T:G	Y149D	1.000
6:116880621:G:A	C153Y	1.000
6:116880622:T:G	C153W	1.000
6:116880654:C:A	A164D	1.000
6:116880659:T:C	F166L	1.000
6:116880660:T:C	F166S	1.000
6:116880660:T:G	F166C	1.000
6:116880661:T:A	F166L	1.000
6:116880661:T:G	F166L	1.000
6:116880662:G:A	G167R	1.000
6:116880662:G:C	G167R	1.000
6:116880663:G:A	G167E	1.000
6:116880663:G:T	G167V	1.000
6:116882371:T:A	I170N	1.000
6:116882371:T:G	I170S	1.000
6:116882373:C:A	R171S	1.000

dbSNP variants (sampled 300 via entrez): RS1000234708 (6:116902065 G>A), RS1000279683 (6:116916398 T>C), RS1000388403 (6:116894807 G>T), RS1000414675 (6:116898598 T>C), RS1000502339 (6:116912368 TA>T,TAA), RS1000504792 (6:116884233 C>T), RS1000587145 (6:116901779 C>T), RS1000650401 (6:116876165 T>C), RS1000721746 (6:116896587 C>T), RS1000795269 (6:116896253 G>T), RS1000836637 (6:116918423 G>A), RS1000946797 (6:116888061 G>A), RS1000971758 (6:116917992 A>C,T), RS1000972920 (6:116903656 C>T), RS1000995305 (6:116903599 G>A)

Disease associations

OMIM: gene MIM:612659 | disease phenotypes: MIM:615710

GenCC curated gene-disease

Disease	Classification	Inheritance
Martinez-Frias syndrome	Definitive	Autosomal recessive
Mitchell-Riley syndrome	Strong	Autosomal recessive
hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
monogenic diabetes	Definitive	AD

Mondo (5): hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome (MONDO:0017400), monogenic diabetes (MONDO:0015967), diabetes mellitus (MONDO:0005015), (MONDO:0014315), Martinez-Frias syndrome (MONDO:0011042)

Orphanet (2): Hypoplastic pancreas-intestinal atresia-hypoplastic gallbladder syndrome (Orphanet:293864), Rare genetic diabetes mellitus (Orphanet:183625)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000819	Diabetes mellitus
HP:0001396	Cholestasis
HP:0001511	Intrauterine growth retardation
HP:0001541	Ascites
HP:0001545	Anteriorly placed anus
HP:0001734	Annular pancreas
HP:0002014	Diarrhea
HP:0002024	Malabsorption
HP:0002245	Meckel diverticulum
HP:0002247	Duodenal atresia
HP:0002566	Intestinal malrotation
HP:0002594	Pancreatic hypoplasia
HP:0002904	Hyperbilirubinemia
HP:0003074	Hyperglycemia
HP:0003577	Congenital onset
HP:0005235	Jejunal atresia
HP:0005912	Biliary atresia
HP:0011467	Absent gallbladder
HP:0011985	Acholic stools

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000750_4	Prostate cancer	2.000000e-12
GCST003148_8	Prostate cancer	4.000000e-11
GCST003602_8	Inflammatory bowel disease	5.000000e-06
GCST004623_99	Neutrophil percentage of granulocytes	4.000000e-09
GCST004748_50	Lung cancer	5.000000e-06
GCST005989_17	Serum total protein levels	2.000000e-08
GCST006014_12	Creatine kinase levels	6.000000e-15
GCST007094_65	Diastolic blood pressure	4.000000e-09
GCST007692_121	Chronic obstructive pulmonary disease	8.000000e-09
GCST008363_113	Offspring birth weight	5.000000e-08
GCST008839_448	Height	8.000000e-11
GCST008860_15	Prostate cancer	9.000000e-15
GCST010241_439	Apolipoprotein A1 levels	1.000000e-11
GCST011320_11	Type 2 diabetes or prostate cancer (pleiotropy)	4.000000e-08
GCST90002381_160	Eosinophil count	5.000000e-10
GCST90002382_352	Eosinophil percentage of white cells	3.000000e-15
GCST90011899_47	Aspartate aminotransferase levels	4.000000e-14

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0007994	neutrophil percentage of granulocytes
EFO:0004534	creatine kinase measurement
EFO:0006336	diastolic blood pressure
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003920	Diabetes Mellitus	C18.452.394.750; C19.246
C563346	Martinez-Frias Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
terbufos	increases methylation	1
ferrous chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, affects response to substance, increases expression	1
bisphenol S	decreases methylation	1
imeglimin	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Acetaminophen	decreases expression	1
Carbamazepine	affects expression	1
Fonofos	increases methylation	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Parathion	increases methylation	1
Tretinoin	increases expression	1
Valproic Acid	affects expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00044746	PHASE4	COMPLETED	Study Evaluating the Safety and Efficacy of Piperacillin/Tazobactam and Ampicillin/Sulbactam in Patients With Diabetic Foot Infections
NCT00069602	PHASE4	COMPLETED	Assessing Continuous Glucose Monitors in Healthy Children
NCT00079638	PHASE4	COMPLETED	Comparative Efficacy Evaluation of Lipids When Treated With Niaspan & Statin or Other Lipid-Modifying Therapies-COMPELL
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00108615	PHASE4	COMPLETED	Effects of Insulin Sensitizers in Subjects With Impaired Glucose Tolerance
NCT00117780	PHASE4	COMPLETED	Comparison of Insulin Detemir Given Once or Twice Daily in Type 1 Diabetes
NCT00120341	PHASE4	COMPLETED	Anodyne Therapy in Diabetic Sensory Neuropathy
NCT00121355	PHASE4	COMPLETED	Novofine Autocover Safety Needle Versus BD Safety Glide
NCT00135226	PHASE4	ACTIVE_NOT_RECRUITING	ASCEND: A Study of Cardiovascular Events iN Diabetes
NCT00144937	PHASE4	UNKNOWN	Multifactorial Intervention on Cardiovascular Risk Factors in Subjects With Peripheral Arterial Disease
NCT00147251	PHASE4	COMPLETED	Stop Atherosclerosis in Native Diabetics Study
NCT00157638	PHASE4	COMPLETED	Integrating Family Medicine and Pharmacy to Advance Primary Care Therapeutics
NCT00162344	PHASE4	COMPLETED	A Study of Stress Heart Imaging in Patients With Diabetes at Risk for Coronary Disease.
NCT00177138	PHASE4	TERMINATED	Use of Campath for Induction and Maintenance Therapy in Pancreas After Kidney Transplantation
NCT00182494	PHASE4	UNKNOWN	Diabetes Prevention Program in Schizophrenia [DPPS]
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00202618	PHASE4	UNKNOWN	Rationale and Design for Shiga Microalbuminuria Reduction Trial
NCT00209170	PHASE4	COMPLETED	Depression-Diabetes Mechanisms: Urban African Americans
NCT00209417	PHASE4	TERMINATED	Renal Effects of Two Iodinated Contrast Media in Patients at Risk Undergoing Computed Tomography
NCT00212004	PHASE4	TERMINATED	Pioglitazone Protects Diabetes Mellitus (DM) Patients Against Re-Infarction (PPAR Study)
NCT00219440	PHASE4	COMPLETED	A Portion-controlled Diet Will Prevent Weight Gain in Diabetics Treated With ACTOS
NCT00225849	PHASE4	UNKNOWN	Japanese Primary Prevention Project With Aspirin
NCT00231894	PHASE4	COMPLETED	Pioglitazone as a Treatment for Lipid and Glucose Abnormalities In Patients With Schizophrenia
NCT00234871	PHASE4	COMPLETED	Tarka® vs. Lotrel® in Hypertensive, Diabetic Subjects With Renal Disease (TANDEM)
NCT00235014	PHASE4	COMPLETED	A Study for Prevention of Kidney Disease in Diabetic Patients (BENEDICT)
NCT00236379	PHASE4	COMPLETED	A Study of the Effects of Risperidone and Olanzapine on Blood Glucose (Sugar) in Patients With Schizophrenia or Schizoaffective Disorder
NCT00241904	PHASE4	COMPLETED	Reducing Total Cardiovascular Risk in an Urban Community
NCT00263393	PHASE4	COMPLETED	Rural Andhra Pradesh Cardiovascular Prevention Study (RAPCAPS)
NCT00264901	PHASE4	COMPLETED	Comparison of Self Adjustment Versus Standard of Care Treatment in Subjects With Type 2 Diabetes
NCT00274274	PHASE4	COMPLETED	Efficacy and Safety of a Fixed or a Flexible Supplementary Insulin Therapy in Type 2 Diabetes
NCT00282451	PHASE4	COMPLETED	Effect of Biphasic Insulin Compared to Biphasic Insulin Combined With Insulin Aspart, With or Without Metformin in Type 2 Diabetes
NCT00282659	PHASE4	COMPLETED	The Use of Magnesium to Improve Blood Pressure, Cholesterol, and Glucose Control
NCT00287820	PHASE4	COMPLETED	Comparative Effects of Chronic Treatment With Olanzapine and Risperidone on Glucose and Lipid Metabolism
NCT00295555	PHASE4	COMPLETED	Doxazosin Effects on ABPM in Hypertensive Patients With Diabetic Nephropathy
NCT00299169	PHASE4	TERMINATED	Randomized Trial Comparing N of 1 Trials to Standard Practice to Improve Adherence to Statins in Patients With Diabetes
NCT00301392	PHASE4	COMPLETED	Japan Prevention Trial of Diabetes by Pitavastatin in Patients With Impaired Glucose Tolerance (J-PREDICT)
NCT00306696	PHASE4	COMPLETED	Examining the Effect of Different Diuretics on Fluid Retention in Diabetics Treated With Rosiglitazone.
NCT00309465	PHASE4	COMPLETED	Perioperative Insulin Glargine Dosing Study