SEMA3C

Chr 7

semaphorin 3C

Also known as: SEMAE, SemE

NCBI Gene: 10512ENSG00000075223UniProt: Q99985

This gene encodes a secreted glycoprotein that belongs to the semaphorin class 3 family of neuronal guidance cues. The encoded protein contains an N-terminal sema domain, integrin and immunoglobulin-like domains, and a C-terminal basic domain. Homodimerization and proteolytic cleavage of the C-terminal propeptide are necessary for the function of the encoded protein. It binds a neuropilin co-receptor before forming a heterotrimeric complex with an associated plexin. An increase in the expression of this gene correlates with an increase in cancer cell invasion and adhesion. Naturally occurring mutations in this gene are associated with Hirschsprung disease. [provided by RefSeq, May 2017]

271
ClinVar variants
16
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SEMA3C
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
16 Pathogenic / Likely Pathogenic· 163 VUS of 271 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.52LOEUF
pLI 0.001
Z-score 3.96
OE 0.32 (0.21–0.52)
Moderately constrained

More LoF-intolerant than ~75% 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.
0.99Z-score
OE missense 0.86 (0.79–0.94)
362 obs / 419.3 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.0.32 (0.21–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.79–0.94)
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.0.93
0≤1.21.6
LoF obs/exp: 13 / 40.0Missense obs/exp: 362 / 419.3Syn Z: 0.65

ClinVar Variant Classifications

271 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
Likely Pathogenic2
VUS163
Likely Benign74
Benign15
Conflicting3
14
Pathogenic
2
Likely Pathogenic
163
VUS
74
Likely Benign
15
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
14
0
14
Likely Pathogenic
0
0
2
0
2
VUS
2
142
19
0
163
Likely Benign
0
3
24
47
74
Benign
0
3
4
8
15
Conflicting
—3
Total21486355271

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

View in ClinVar →

Protein Context — Lollipop Plot

SEMA3C · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
SEMAPHORIN 3C; SEMA3C
MIM #602645 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Single-cell transcriptomic profiles in the pathophysiology within the microenvironment of early diabetic kidney disease.
Tsai YC et al.·Cell Death Dis
2023
Semaphorin 3C exacerbates liver fibrosis.
De Angelis Rigotti F et al.·Hepatology
2023
SEMA3C regulates tumor-associated macrophage phenotype and influences lung cancer cell migration and invasion through VNN1.
Liu R et al.·Hum Exp Toxicol
2025
Uncovering endothelial to mesenchymal transition drivers in atherosclerosis via multi-omics analysis.
Huang Q et al.·BMC Cardiovasc Disord
2025
Dependency of Tamoxifen Sensitive and Resistant ER(+) Breast Cancer Cells on Semaphorin 3C (SEMA3C) for Growth.
Bhasin S et al.·Cells
2023
Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma.
Hao J et al.·Nat Commun
2023
LETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C.
Ducoli L et al.·Nat Commun
2021
Sema3C promotes hepatic metastasis and predicts poor prognosis in gastric adenocarcinoma.
Li M et al.·J Int Med Res
2021
FOXM1: Functional Roles of FOXM1 in Non-Malignant Diseases.
Zhang Z et al.·Biomolecules
2023Review
High level of Sema3C is associated with glioma malignancy.
Vaitkienė P et al.·Diagn Pathol
2015
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools