NONO

Chr XX-linked

non-POU domain containing octamer binding

Also known as: MRXS34, NMT55, NRB54, P54, P54NRB, PPP1R114

NCBI Gene: 4841 ENSG00000147140 UniProt: Q15233 OMIM: 300084

This protein is a DNA- and RNA-binding protein involved in pre-mRNA splicing, transcriptional regulation, DNA repair, and nuclear paraspeckle formation. Mutations cause X-linked syndromic intellectual developmental disorder. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.24), indicating that protein function is critical for normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismX-linkedLOEUF 0.241 OMIM phenotype

Clinical Summary— NONO

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Gene-Disease Validity (ClinGen)

X-linked syndromic intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

64 unique Pathogenic / Likely Pathogenic· 109 VUS of 300 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NONO

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.24LOEUF

pLI 0.993

Z-score 3.87

OE 0.05 (0.02–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

3.59Z-score

OE missense 0.27 (0.22–0.34)

52 obs / 191.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.05 (0.02–0.24)

0≤0.351.4

Missense OE0.27 (0.22–0.34)

0≤0.61.4

Synonymous OE0.95

0≤1.21.6

LoF obs/exp: 1 / 19.4Missense obs/exp: 52 / 191.9Syn Z: 0.32

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNONO-related syndromic intellectual disabilityLOFXLR

0.3196th %ile

GOF

0.3491th %ile

LOF

0.82top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 33% of P/LP variants are LoF · LOEUF 0.24

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

300 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic52

Likely Pathogenic12

VUS109

Likely Benign52

Benign16

Conflicting4

Pathogenic

Likely Pathogenic

109

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	0	40	0	52
Likely Pathogenic	9	0	3	0	12
VUS	2	86	19	2	109
Likely Benign	0	3	22	27	52
Benign	1	0	13	2	16
Conflicting	—				4
Total	24	89	97	31	245

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

View in ClinVar →

Protein Context — Lollipop Plot

NONO · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — NONO

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Hematological Malignancies

Exploratory Study on in Vivo CAR-T Therapy Targeting CD20 for the Treatment of Hematological Malignancies

NOT YET RECRUITING

NCT07362602Phase EARLY_PHASE1The 923rd Hospital of Joint Logistics Support Force of People's Liberation ArmyStarted 2026-01-26

In vivo CAR-T drug targeting CD20 based on mRNA-LNP

Discordant Cancers

Genomic Analysis of Families With a History of Discordant Cancers

RECRUITING

NCT04860453Case Comprehensive Cancer CenterStarted 2020-11-17

WES via Illumina NextSeq 550 sequencing systemBlood DrawSkin biopsy

Skin MicrobiomeGraft Versus Host DiseaseGraft Versus Host Disease in Skin

The Skin Microbiome in Graft Versus Host Disease

ACTIVE NOT RECRUITING

NCT04231500University Hospital, Basel, SwitzerlandStarted 2023-03-01

Skin swabsSkin punch biopsiesadditional blood sampling

Sleep ApneaSleep-Disordered Breathing

The Meaning of Dopaminergic Pathway in Sleep Breathing Disorders.

ENROLLING BY INVITATION

NCT05890911Wroclaw Medical UniversityStarted 2023-06-01

PolysomnographyBlood dopamine level measurementGenetical test

Muscular Atrophy, Spinal

A Study Evaluating the Effectiveness and Safety of Risdiplam Administered as an Early Intervention in Pediatric Participants With Spinal Muscular Atrophy After Gene Therapy

RECRUITING

NCT05861986Phase PHASE4Hoffmann-La RocheStarted 2024-05-30

Risdiplam

Fetal Developmental AbnormalityFetal DevelopmentHuman

Scottish Advanced Fetal Research Study

RECRUITING

NCT04613583University of AberdeenStarted 2016-05-01

SAFeR fetuses

Advanced Solid TumorsEwing SarcomaHepatocellular Carcinoma (HCC)

A Phase 1/1B Study of ST-01156, a Small Molecule RBM39 Degrader, in Patients With Advanced Solid Malignancies

RECRUITING

NCT07197554Phase PHASE1SEED Therapeutics, Inc.Started 2025-12-01

ST-01156

Hairy Cell Leukemia

Binimetinib for People With Relapsed/Refractory BRAF Wild Type Hairy Cell Leukemia and Variant

RECRUITING

NCT04322383Phase PHASE2National Cancer Institute (NCI)Started 2021-01-07

binimetinib

Venous Thromboembolic Disease

Risk Factors of Venous Thromboembolism in Women During Hormonal Exposure

RECRUITING

NCT03206372University Hospital, BrestStarted 2017-10-24

Case groupControl group

Inflammatory Bowel DiseasesColitis, UlcerativeCrohn Disease

Investigation of the Correlation Between Polyamine Levels and Their Key Enzymatic Activities in Association With Inflammatory Bowel Disease Progression

RECRUITING

NCT06995170Xijing HospitalStarted 2025-01-01

Idiopathic Pulmonary Arterial HypertensionHeritable Pulmonary Arterial HypertensionUnaffected Mutation Carriers: Healthy Participants With a Known BMPR2 Gene Mutation and Normal Pulmonary Pressure and RV Function on Echo

Risk and Resilience in Pulmonary Arterial Hypertension and Genetically Susceptible Individuals

RECRUITING

NCT05584722Vanderbilt University Medical CenterStarted 2022-11-01

Migraine

Effectiveness and Tolerability of Zavegepant for Acute Migraine Treatment Among Those Using CGRP Targeting Preventive Medications

RECRUITING

NCT06401642Phase PHASE4Mayo ClinicStarted 2024-03-22

Zavegepant

Clinical Literature