SEMA4B

Chr 15

semaphorin 4B

Also known as: SEMAC, SemC

NCBI Gene: 10509 ENSG00000185033 UniProt: Q9NPR2 OMIM: 617029

The protein inhibits axonal extension by providing local signals that specify territories inaccessible for growing axons, functioning as a guidance cue during neural development. Mutations cause autosomal recessive retinal dystrophy with early childhood onset, primarily affecting vision and retinal function. The gene shows relatively low constraint against loss-of-function variants (pLI = 0.0005, LOEUF = 0.533), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable chemorepellent activity; neuropilin binding activity; and semaphorin receptor binding activity. Predicted to be involved in several processes, including axon guidance; neural crest cell migration; and semaphorin-plexin signaling pathway. Predicted to be located in membrane and synapse. Predicted to be active in glutamatergic synapse and postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.53

Clinical Summary— SEMA4B

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

140 VUS of 166 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.001

Z-score 3.83

OE 0.34 (0.22–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.96Z-score

OE missense 0.88 (0.81–0.95)

430 obs / 489.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.22–0.53)

0≤0.351.4

Missense OE?0.88 (0.81–0.95)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 13 / 38.8Missense obs/exp: 430 / 489.5Syn Z: -1.28

This gene — mechanism propensity

0.6839th %ile

GOF

0.7028th %ile

LOF

0.2872th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

166 submitted variants in ClinVar

ClinVar

Classification Summary

VUS140

Likely Benign10

140

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	140	140
Likely Benign	10	10
Benign	0	0
Total	150	150

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

View in ClinVar →

41 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap SEMA4B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →