RFX3

Chr 9

regulatory factor X3

NCBI Gene: 5991ENSG00000080298UniProt: P48380

This gene is a member of the regulatory factor X gene family, which encodes transcription factors that contain a highly-conserved winged helix DNA binding domain. The protein encoded by this gene is structurally related to regulatory factors X1, X2, X4, and X5. It is a transcriptional activator that can bind DNA as a monomer or as a heterodimer with other RFX family members. Multiple transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2013]

339
ClinVar variants
185
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— RFX3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
185 Pathogenic / Likely Pathogenic· 116 VUS of 339 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
Dual constrained — LoF & missense intolerant
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.
0.10LOEUF
pLI 1.000
Z-score 6.14
OE 0.02 (0.01–0.10)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
3.47Z-score
OE missense 0.53 (0.47–0.59)
223 obs / 424.3 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.02 (0.01–0.10)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.53 (0.47–0.59)
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.1.21
0≤1.21.6
LoF obs/exp: 1 / 45.8Missense obs/exp: 223 / 424.3Syn Z: -2.11

ClinVar Variant Classifications

339 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic169
Likely Pathogenic16
VUS116
Likely Benign17
Benign4
Conflicting2
169
Pathogenic
16
Likely Pathogenic
116
VUS
17
Likely Benign
4
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
169
0
169
Likely Pathogenic
6
1
9
0
16
VUS
4
85
27
0
116
Likely Benign
0
7
4
6
17
Benign
0
0
1
3
4
Conflicting
—2
Total10932109324

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

View in ClinVar →

Protein Context — Lollipop Plot

RFX3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

RFX3-related neurodevelopmental disorder with autism and other behavioural abnormalities

definitive
ADLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Dev. Disorders
G2P ↗
splice region variantsplice donor variantframeshift variantstop gainedmissense variantinframe deletionwhole partial gene deletion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.
Harris HK et al.·Genet Med
2021
Whole-genome sequencing reveals individual and cohort level insights into chromosome 9p syndromes.
Wang Y et al.·Genome Med
2025Cohort
Common variant of BCAS3 is associated with gout risk in Japanese population: the first replication study after gout GWAS in Han Chinese.
Sakiyama M et al.·BMC Med Genet
2018
Histone H2B monoubiquitination regulates heart development via epigenetic control of cilia motility.
Robson A et al.·Proc Natl Acad Sci U S A
2019
Genome-wide analysis of PDX1 target genes in human pancreatic progenitors.
Wang X et al.·Mol Metab
2018
Identification of RFX5 as prognostic biomarker and associated with immune infiltration in stomach adenocarcinoma.
Guo L et al.·Eur J Med Res
2022
Distal 1q Duplication and Distal 9p Deletion: A Follow-Up Case Report and Literature Review on Candidate Genes for 9p Deletion Syndrome.
Helbig J et al.·Am J Med Genet A
2025Review
Evidence that 6q25.1 variant rs6931104 confers susceptibility to chronic myeloid leukemia through RMND1 regulation.
Woo YM et al.·PLoS One
2019
SPEN, a new player in primary cilia formation and cell migration in breast cancer.
Légaré S et al.·Breast Cancer Res
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools