SEMA6B

Chr 19AD

semaphorin 6B

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

NCBI Gene: 10501 ENSG00000167680 UniProt: Q9H3T3 OMIM: 608873

The protein is a transmembrane semaphorin that guides axon development in both peripheral and central nervous systems. Gain-of-function mutations cause progressive myoclonic epilepsy type 11 with autosomal dominant inheritance. The pathogenic mechanism involves abnormal neuronal connectivity due to disrupted axonal guidance signaling.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Epilepsy, progressive myoclonic, 11MIM #618876

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · progressive myoclonus epilepsy · AD · ClinGen 2025

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.46

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

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?

LoF OE?0.26 (0.16–0.46)

0≤0.351.4

Missense OE?0.70 (0.64–0.77)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 9 / 34.0Missense obs/exp: 310 / 441.2Syn Z: -0.38

Background carrier burden — how many people carry a rare variant somewhere in SEMA6B?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 48

1,368 rare PASS variants

Rare truncating (LoF)

1 in 960

166 rare PASS variants

Rare synonymous (reference)

1 in 58

712 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SEMA6B. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 59	1 in 1,100
South Asian	~43k	1 in 44	1 in 530
Remaining (unassigned)	~30k	1 in 35	1 in 910
European (Finnish)	~27k	1 in 200	1 in 920
Admixed American	~22k	1 in 38	1 in 460
African / African American	~21k	1 in 33	1 in 1,200
East Asian	~20k	1 in 39	1 in 1,300
Ashkenazi Jewish	~13k	1 in 120	1 in 520
Middle Eastern	~2,884	1 in 40	1 in 540

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 13 of 16 coding exons well covered in gnomAD exomes; exons 2, 3, 17 marginal. Genomes: all 16.? see exons ↓