RFX6

Chr 6AR

regulatory factor X6

Also known as: MTCHRS, MTFS, RFXDC1, dJ955L16.1

NCBI Gene: 222546ENSG00000185002UniProt: Q8HWS3

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.[provided by RefSeq, Sep 2010]

Primary Disease Associations & Inheritance

Mitchell-Riley syndromeMIM #615710
AR
417
ClinVar variants
64
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— RFX6
🧬
Gene-Disease Validity (ClinGen)
monogenic diabetes · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.
📋
ClinVar Variants
64 Pathogenic / Likely Pathogenic· 155 VUS of 417 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.47LOEUF
pLI 0.000
Z-score 4.56
OE 0.31 (0.21–0.47)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.20Z-score
OE missense 0.85 (0.78–0.92)
419 obs / 494.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.31 (0.21–0.47)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.78–0.92)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.03
0≤1.21.6
LoF obs/exp: 16 / 51.2Missense obs/exp: 419 / 494.0Syn Z: -0.32

ClinVar Variant Classifications

417 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45
Likely Pathogenic19
VUS155
Likely Benign129
Benign62
Conflicting7
45
Pathogenic
19
Likely Pathogenic
155
VUS
129
Likely Benign
62
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
0
33
0
45
Likely Pathogenic
6
4
9
0
19
VUS
1
139
14
1
155
Likely Benign
0
17
56
56
129
Benign
0
1
55
6
62
Conflicting
—7
Total1916116763417

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RFX6 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

RFX6-related Martinez-Frias syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitchell-Riley syndrome

MIM #615710

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — RFX6
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort.
Billings LK et al.·Endocrinol Diabetes Metab
2022Cohort
RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function.
Ibrahim H et al.·Diabetologia
2024
Genome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants.
Young WJ et al.·J Am Heart Assoc
2024Meta-analysis
A heterozygous protein-truncating RFX6 variant in a family with childhood-onset, pregnancy-associated and adult-onset diabetes.
Akiba K et al.·Diabet Med
2020Case report
First multivisceral transplantation in Mitchell-Riley/Martinez-Frias syndrome.
Estefanía-Fernández K et al.·Pediatr Transplant
2022Review
Neonatal and early-onset diabetes in Ukraine: Atypical features and mortality.
Globa E et al.·Diabet Med
2023
RFX6 is needed for the development and maintenance of the β-cell phenotype.
Taleb N et al.·Islets
2011
Mitchell-Riley Syndrome: Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations.
Passone CGB et al.·Front Endocrinol (Lausanne)
2022Functional
Systematic meta-analyses of gene-specific genetic association studies in prostate cancer.
Hao Q et al.·Oncotarget
2016Meta-analysis
MODY Only Monogenic? A Narrative Review of the Novel Rare and Low-Penetrant Variants.
Hasballa I et al.·Int J Mol Sci
2024Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
RFX6 expression is central to the development and function of the neuroendocrine compartments of the pancreas and intestine and strongly affects diabetes risk.
Bate TSR et al.·Diabetol Int
2026🔓 Open Access
RFX6 maturity-onset diabetes of the young: clinical considerations and novel use of tirzepatide.
Gopalakrishnan PP et al.·Endocrinol Diabetes Metab Case Rep
2026🔓 Open Access
Multifaceted functions of transcription regulatory factor X6 (RFX6): from pancreatic development to cancer progression.
Ni X et al.·Cancer Cell Int
2025🔓 Open Access
RFX6 heterozygous frame-shift variation causes maturity-onset diabetes mellitus of the young (MODY) with refractory hyperlipidemia: a case report.
Li M et al.·AME Case Rep
2025🔓 Open AccessCase report
Rare forms of monogenic diabetes in non-European individuals. First reports of CEL and RFX6 mutations from the Indian subcontinent.
Marucci A et al.·Acta Diabetol
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation

External Resources

Links to major genomics databases and tools