SEMA6B

Chr 19AD

semaphorin 6B

Also known as: EPM11, SEM-SEMA-Y, SEM-SEMA-Z, SEMA-VIB, SEMAN, semaZ

NCBI Gene: 10501ENSG00000167680UniProt: Q9H3T3

This gene encodes a member of the semaphorin family, a group of proteins characterized by the presence of a conserved semaphorin (sema) domain. Whereas some semaphorins are transmembrane proteins, others are secreted. Semaphorins play a major role in axon guidance. The protein encoded by this gene may be involved in both peripheral and central nervous system development. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Epilepsy, progressive myoclonic, 11MIM #618876
AD
354
ClinVar variants
43
Pathogenic / LP
0.06
pLI score
0
Active trials
Clinical Summary— SEMA6B
🧬
Gene-Disease Validity (ClinGen)
progressive myoclonus epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
43 Pathogenic / Likely Pathogenic· 223 VUS of 354 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

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.
0.46LOEUF
pLI 0.062
Z-score 3.97
OE 0.26 (0.16–0.46)
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.
2.22Z-score
OE missense 0.70 (0.64–0.77)
310 obs / 441.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.26 (0.16–0.46)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.64–0.77)
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.1.03
0≤1.21.6
LoF obs/exp: 9 / 34.0Missense obs/exp: 310 / 441.2Syn Z: -0.38

ClinVar Variant Classifications

354 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic18
VUS223
Likely Benign71
Benign13
Conflicting4
25
Pathogenic
18
Likely Pathogenic
223
VUS
71
Likely Benign
13
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
0
17
0
25
Likely Pathogenic
8
4
6
0
18
VUS
9
193
20
1
223
Likely Benign
0
41
1
29
71
Benign
0
2
7
4
13
Conflicting
—4
Total252405134354

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

View in ClinVar →

Protein Context — Lollipop Plot

SEMA6B · protein map & ClinVar variants

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

Gene2Phenotype Curations

SEMA6B-related neurodevelopmental disorder

moderate
ADUndeterminedIncreased Gene Product Level
Dev. Disorders
G2P ↗
frameshift variant NMD escaping

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
SEMAPHORIN 6B; SEMA6B
MIM #608873 · *

Epilepsy, progressive myoclonic, 11

MIM #618876

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Identification and validation of a novel senescence-related biomarker for thyroid cancer to predict the prognosis and immunotherapy.
Hong K et al.·Front Immunol
2023
SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance.
Cordovado A et al.·Hum Mol Genet
2022
A De Novo SEMA6B Variant in a Chinese Patient with Progressive Myoclonic Epilepsy-11 and Review of the Literature.
Li Q et al.·J Mol Neurosci
2021Review
Autism, Electrical Status Epilepticus in Sleep, and a Likely Pathogenic SEMA6B Variant.
Ibrahim A et al.·Pediatrics
2025Case report
Progressive Myoclonus Epilepsy and Beyond: A Systematic Review of SEMA6B-related Disorders.
Altıntaş M et al.·Neuropediatrics
2025Case report
Aberrant expression of semaphorin 6B affects cell phenotypes in thyroid carcinoma by activating the Notch signalling pathway.
Lv XJ et al.·Endokrynol Pol
2021
The natural history of progressive myoclonus ataxia.
van der Veen S et al.·Neurobiol Dis
2024Natural history
Systematic analysis of variants escaping nonsense-mediated decay uncovers candidate Mendelian diseases.
Torene RI et al.·Am J Hum Genet
2024
Increased SEMA6B expression as a potential prognostic and immune cell infiltration biomarker in thyroid cancer patients.
Lei Q et al.·Aging (Albany NY)
2023Cohort
Serum Proteomics Uncovers Biomarkers of Clinical Portal Hypertension in Children With Biliary Atresia.
Osborn J et al.·Hepatol Commun
2022
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