SEMA5A

Chr 5

semaphorin 5A

Also known as: SEMAF, semF

NCBI Gene: 9037ENSG00000112902UniProt: Q13591OMIM: 609297

The protein functions as a bifunctional axonal guidance cue during neural development, with attractive effects mediated by heparan sulfate proteoglycans and inhibitory effects through chondroitin sulfate proteoglycans. Mutations in this gene have been associated with autism spectrum disorders, following autosomal dominant inheritance. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to have significant clinical effects.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.48
Clinical Summary— SEMA5A
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
101 unique Pathogenic / Likely Pathogenic· 176 VUS of 381 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.48LOEUF
pLI 0.000
Z-score 4.79
OE 0.33 (0.23–0.48)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
1.33Z-score
OE missense 0.86 (0.80–0.92)
573 obs / 670.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.33 (0.23–0.48)
0≤0.351.4
Missense OE0.86 (0.80–0.92)
0≤0.61.4
Synonymous OE1.10
0≤1.21.6
LoF obs/exp: 20 / 60.1Missense obs/exp: 573 / 670.1Syn Z: -1.33
DN
0.6744th %ile
GOF
0.6542th %ile
LOF
0.3356th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

381 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic101
VUS176
Likely Benign49
Benign26
Conflicting3
101
Pathogenic
176
VUS
49
Likely Benign
26
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
101
0
101
Likely Pathogenic
0
0
0
0
0
VUS
2
157
16
1
176
Likely Benign
0
6
12
31
49
Benign
0
3
1
22
26
Conflicting
—3
Total216613054355

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

View in ClinVar →

Protein Context — Lollipop Plot

SEMA5A · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Circulating small extracellular vesicle-encapsulated SEMA5A-IT1 attenuates myocardial ischemia-reperfusion injury after cardiac surgery with cardiopulmonary bypass
Wu T et al.·Cell Mol Biol Lett
2022
SnRNA-Seq analysis reveals ten hub genes associated with alveolar epithelial cell injury during pulmonary acute respiratory distress syndrome
Chen H et al.·Heliyon
2023
Hsa-miR-21-5p is induced by interleukin-6 and affects multiple pathogenic factors associated with fibroblast-like synoviocytes in rheumatoid arthritis
Araki K et al.·Sci Rep
2025
Do Semaphorins Play a Role in Development of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease?
Šamadan L et al.·Biomedicines
2022Cohort
Extracellular domain of semaphorin 5A serves a tumor-suppressing role by activating interferon signaling pathways in lung adenocarcinoma cells.
Chen MZ et al.·Int J Oncol
2022
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

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