SEMA3A

Chr 7

semaphorin 3A

Also known as: COLL1, HH16, Hsema-I, Hsema-III, SEMA1, SEMAD, SEMAIII, SEMAL

NCBI Gene: 10371ENSG00000075213UniProt: Q14563

This gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema domain. This secreted protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites. In both cases, the protein is vital for normal neuronal pattern development. Increased expression of this protein is associated with schizophrenia and is seen in a variety of human tumor cell lines. Also, aberrant release of this protein is associated with the progression of Alzheimer's disease. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

UniProtHypogonadotropic hypogonadism 16 with or without anosmia
413
ClinVar variants
24
Pathogenic / LP
0.98
pLI score· haploinsufficient
1
Active trials
Clinical Summary— SEMA3A
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
24 Pathogenic / Likely Pathogenic· 212 VUS of 413 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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.
0.31LOEUF
pLI 0.978
Z-score 5.27
OE 0.17 (0.10–0.31)
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.
1.75Z-score
OE missense 0.76 (0.70–0.83)
327 obs / 429.0 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.0.17 (0.10–0.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.70–0.83)
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.0.95
0≤1.21.6
LoF obs/exp: 8 / 47.0Missense obs/exp: 327 / 429.0Syn Z: 0.51

ClinVar Variant Classifications

413 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic8
VUS212
Likely Benign110
Benign62
Conflicting5
16
Pathogenic
8
Likely Pathogenic
212
VUS
110
Likely Benign
62
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
16
0
16
Likely Pathogenic
2
0
6
0
8
VUS
2
175
34
1
212
Likely Benign
1
11
40
58
110
Benign
0
0
56
6
62
Conflicting
—5
Total518615265413

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

View in ClinVar →

Protein Context — Lollipop Plot

SEMA3A · protein map & ClinVar variants

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

Gene2Phenotype Curations

SEMA3A-related skeletal dysplasia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — SEMA3A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC.
Lupo F et al.·Gut
2024
The sema domain.
Gherardi E et al.·Curr Opin Struct Biol
2004Review
Exploring potential genes and mechanisms linking erectile dysfunction and depression.
Yuan P et al.·Front Endocrinol (Lausanne)
2023Functional
Semaphorins and its receptors: Emerging cellular biomarkers and therapeutic targets in autoimmune and inflammatory disorders.
Qamar T et al.·Life Sci
2025Review
Prevalence of pathogenic variants and digenic disease in patients diagnosed with normosmic hypogonadotropic hypogonadism/Kallmann Syndrome.
Poch A et al.·Mol Cell Endocrinol
2024Cohort
New targets in diabetic retinopathy: addressing limitations of current treatments through the Sema3A/Nrp1 pathway.
Sivaprasad S et al.·Eye (Lond)
2025Review
Semaphorin3a promotes advanced diabetic nephropathy.
Aggarwal PK et al.·Diabetes
2015
Novel and recurrent genetic variants associated with male and female infertility.
Jankowska KK et al.·J Appl Genet
2025
Genetic spectrum of Kallmann syndrome: Single-center experience and systematic review.
Patil VA et al.·Clin Endocrinol (Oxf)
2022Review
Clinical and Genetic Characterization of a Constitutional Delay of Growth and Puberty Cohort.
Barroso PS et al.·Neuroendocrinology
2020Cohort
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
Alport Syndrome

BAY3401016; Biomarker Study Alport

NOT YET RECRUITING
NCT07211685Phase PHASE2BayerStarted 2025-12-02
BAY 3401016Placebo

External Resources

Links to major genomics databases and tools