PLXNA3

Chr X

plexin A3

Also known as: 6.3, HSSEXGENE, PLXN3, PLXN4, XAP-6

NCBI Gene: 55558 ENSG00000130827 UniProt: P51805

The protein functions as a coreceptor for class 3 semaphorins and is essential for axon guidance, cytoskeletal remodeling, and proper dendrite spine morphology in the developing nervous system. Mutations cause neurodevelopmental disorders with intellectual disability and autism spectrum features, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants, indicating intolerance to protein-disrupting mutations.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the plexin class of proteins. The encoded protein is a class 3 semaphorin receptor, and may be involved in cytoskeletal remodeling and as well as apoptosis. Studies of a similar gene in zebrafish suggest that it is important for axon pathfinding in the developing nervous system. This gene may be associated with tumor progression. [provided by RefSeq, Aug 2013]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.38

Clinical Summary— PLXNA3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

145 VUS of 381 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?

0.38LOEUF

pLI 0.055

Z-score 5.39

OE 0.25 (0.17–0.38)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.68Z-score

OE missense 0.94 (0.89–0.99)

853 obs / 910.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.17–0.38)

0≤0.351.4

Missense OE?0.94 (0.89–0.99)

0≤0.61.4

Synonymous OE?1.31

0≤1.21.6

LoF obs/exp: 15 / 60.1Missense obs/exp: 853 / 910.4Syn Z: -4.98

This gene — mechanism propensity

0.6358th %ile

GOF

0.6639th %ile

LOF

0.3356th %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

381 submitted variants in ClinVar

ClinVar

Classification Summary

VUS145

Likely Benign87

145

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	140	3	2	145
Likely Benign	2	22	63	87
Benign	0	0	0	0
Total	142	25	65	232

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap PLXNA3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →