SETD5

Chr 3AD

SET domain containing 5

Also known as: MRD23, SETD5A

NCBI Gene: 55209ENSG00000168137UniProt: Q9C0A6

This function of this gene has yet to be determined but based on sequence similarity to other SET domain proteins it may function as a histone methyltransferase. Mutations in this gene have been associated with an autosomal dominant form of intellectual disability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 23MIM #615761
AD
478
ClinVar variants
99
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— SETD5
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Gene-Disease Validity (ClinGen)
syndromic complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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
99 Pathogenic / Likely Pathogenic· 264 VUS of 478 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.23LOEUF
pLI 1.000
Z-score 6.70
OE 0.13 (0.08–0.23)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
1.13Z-score
OE missense 0.89 (0.83–0.94)
683 obs / 771.5 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.0.13 (0.08–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.83–0.94)
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.1.05
0≤1.21.6
LoF obs/exp: 9 / 69.1Missense obs/exp: 683 / 771.5Syn Z: -0.68

ClinVar Variant Classifications

478 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic61
Likely Pathogenic38
VUS264
Likely Benign100
Benign6
Conflicting9
61
Pathogenic
38
Likely Pathogenic
264
VUS
100
Likely Benign
6
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
25
3
33
0
61
Likely Pathogenic
23
6
9
0
38
VUS
1
238
24
1
264
Likely Benign
0
23
27
50
100
Benign
0
0
0
6
6
Conflicting
—9
Total492709357478

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

View in ClinVar →

Protein Context — Lollipop Plot

SETD5 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SETD5-related intellectual developmental disorder

definitive
ADLoss 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

Intellectual developmental disorder, autosomal dominant 23

MIM #615761

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.
Grozeva D et al.·Hum Mutat
2015
Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
De Falco A et al.·Eur J Paediatr Neurol
2025Cohort
De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.
Pande S et al.·Eur J Hum Genet
2024Cohort
Expanding the Genotype and Phenotype of SETD5-Related Neurodevelopmental Syndrome.
Ahsan N et al.·Pediatr Neurol
2023
Genetic variations on SETD5 underlying autistic conditions.
Fernandes IR et al.·Dev Neurobiol
2018
SETD5 facilitates stemness and represses ferroptosis via m6A-mediating PKM2 stabilization in non-small cell lung cancer.
Liu X et al.·Oncogene
2025
Expansion of the Genotypic and Phenotypic Spectrum of SETD5 Disorder Using Data From the National Brain Gene Registry.
Callahan NC et al.·Clin Genet
2025
A Case of a Fetus With SETD5 Mutation: Prenatal Phenotype and Literature Review.
Fan J et al.·Birth Defects Res
2025Review
The Brain Gene Registry: a data snapshot.
Baldridge D et al.·J Neurodev Disord
2024
Whole Genome Sequencing of "Mutation-Negative" Individuals With Cornelia de Lange Syndrome.
Ansari M et al.·Hum Mutat
2025
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