SEMA5A

Chr 5

semaphorin 5A

Also known as: SEMAF, semF

NCBI Gene: 9037 ENSG00000112902 UniProt: Q13591

The protein functions as a bifunctional axonal guidance cue during neural development, with attractive effects mediated by heparan sulfate proteoglycans and inhibitory effects through chondroitin sulfate proteoglycans. Mutations in this gene have been associated with autism spectrum disorders, following autosomal dominant inheritance. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to have significant clinical effects.

ResearchSummary from RefSeq, UniProt

This gene belongs to the semaphorin gene family that encodes membrane proteins containing a semaphorin domain and several thrombospondin type-1 repeats. Members of this family are involved in axonal guidance during neural development. This gene has been implicated as an autism susceptibility gene.[provided by RefSeq, Jan 2010]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.48

Clinical Summary— SEMA5A

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

163 VUS of 264 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.000

Z-score 4.79

OE 0.33 (0.23–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.33Z-score

OE missense 0.86 (0.80–0.92)

573 obs / 670.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.23–0.48)

0≤0.351.4

Missense OE?0.86 (0.80–0.92)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 20 / 60.1Missense obs/exp: 573 / 670.1Syn Z: -1.33

This gene — mechanism propensity

0.6744th %ile

GOF

0.6542th %ile

LOF

0.3356th %ile

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

DNprediction above median

GOFprediction 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

264 submitted variants in ClinVar

ClinVar

Classification Summary

VUS163

Likely Benign46

Benign26

Conflicting3

163

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	2	157	3	1	163
Likely Benign	0	6	9	31	46
Benign	0	3	1	22	26
Conflicting	—				3
Total	2	166	13	54	238

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

View in ClinVar →

102 pathogenic / likely-pathogenic (of 118) ClinVar copy-number / structural variants overlap SEMA5A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →