SEMA6A

Chr 5

semaphorin 6A

Also known as: HT018, SEMA, SEMA6A1, SEMAQ, VIA

NCBI Gene: 57556ENSG00000092421UniProt: Q9H2E6

Predicted to enable identical protein binding activity; signaling receptor binding activity; and transmembrane signaling receptor activity. Involved in cellular response to vascular endothelial growth factor stimulus; negative regulation of cell adhesion involved in sprouting angiogenesis; and negative regulation of signal transduction. Predicted to be located in axon and membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

200
ClinVar variants
25
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SEMA6A
⚡
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
25 Pathogenic / Likely Pathogenic· 160 VUS of 200 total submissions

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.
0.22LOEUF
pLI 1.000
Z-score 5.39
OE 0.10 (0.05–0.22)
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.
0.75Z-score
OE missense 0.91 (0.85–0.98)
543 obs / 594.2 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.0.10 (0.05–0.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.85–0.98)
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.1.10
0≤1.21.6
LoF obs/exp: 4 / 41.4Missense obs/exp: 543 / 594.2Syn Z: -1.23

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic2
VUS160
Likely Benign9
Benign5
Conflicting1
23
Pathogenic
2
Likely Pathogenic
160
VUS
9
Likely Benign
5
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
23
0
23
Likely Pathogenic
0
1
1
0
2
VUS
0
155
5
0
160
Likely Benign
0
5
2
2
9
Benign
0
0
0
5
5
Conflicting
—1
Total0161317200

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

View in ClinVar →

Protein Context — Lollipop Plot

SEMA6A · 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 6A; SEMA6A
MIM #605885 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability.
Lettieri A et al.·Nat Commun
2023
Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.
Aung T et al.·Nat Genet
2017Meta-analysis
Correlation of Long Noncoding RNA SEMA6A-AS1 Expression with Clinical Outcome in HBV-Related Hepatocellular Carcinoma.
Yu S et al.·Clin Ther
2020
Genome-Wide Association Study Identifies 4 Novel Risk Loci for Small Intestinal Neuroendocrine Tumors Including a Missense Mutation in LGR5.
Giri AK et al.·Gastroenterology
2023
Semaphorin 6A Attenuates the Migration Capability of Lung Cancer Cells via the NRF2/HMOX1 Axis.
Chen LH et al.·Sci Rep
2019
The class 6 semaphorin SEMA6A is induced by interferon-gamma and defines an activation status of langerhans cells observed in pathological situations.
Gautier G et al.·Am J Pathol
2006
Genetics of ANCA-associated vasculitides: HLA and beyond.
Alberici F et al.·Clin Exp Rheumatol
2014Review
From plasma membrane to cytoskeleton: a novel function for semaphorin 6A.
Prislei S et al.·Mol Cancer Ther
2008
Alu Deletions in LAMA2 and CDH4 Genes Are Key Components of Polygenic Predictors of Longevity.
Erdman VV et al.·Int J Mol Sci
2022
Male-specific association of the FCGR2A His167Arg polymorphism with Kawasaki disease.
Kwon YC et al.·PLoS One
2017
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