PLXNA1

Chr 3AR

plexin A1

Also known as: DWOPNED, NOV, NOVP, PLEXIN-A1, PLXN1

NCBI Gene: 5361 ENSG00000114554 UniProt: Q9UIW2 OMIM: 601055

PLXNA1 encodes a coreceptor for class 3 semaphorins that is essential for axon guidance and cytoskeletal remodeling during nervous system development. Biallelic mutations cause Dworschak-Punetha neurodevelopmental syndrome, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants, indicating its critical role in normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Predicted to enable semaphorin receptor activity. Predicted to be involved in several processes, including T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell; nervous system development; and semaphorin-plexin signaling pathway. Predicted to act upstream of or within dichotomous subdivision of terminal units involved in salivary gland branching; neuron projection extension; and regulation of smooth muscle cell migration. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.261 OMIM phenotype

Clinical Summary— PLXNA1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 523 VUS of 1054 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.26LOEUF

pLI 1.000

Z-score 7.21

OE 0.17 (0.11–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.45Z-score

OE missense 0.73 (0.69–0.77)

928 obs / 1274.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.17 (0.11–0.26)

0≤0.351.4

Missense OE?0.73 (0.69–0.77)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 15 / 88.1Missense obs/exp: 928 / 1274.4Syn Z: -1.34

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedPLXNA1-related neurodevelopmental disorderLOFAR

limitedPLXNA1-related neurodevelopmental disorder with seizuresOTHERAD

This gene — mechanism propensity

0.4091th %ile

GOF

0.5660th %ile

LOF

0.60top 25%

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

LOF76% of P/LP variants are LoF · LOEUF 0.26

DN1 literature citation

Literature Evidence

DNConclusion: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerizatio1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 34054129 ↗

ClinVar Variant Classifications

1054 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic12

VUS523

Likely Benign425

Benign51

Conflicting11

Pathogenic

Likely Pathogenic

523

VUS

425

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	0	0	0	5
Likely Pathogenic	8	4	0	0	12
VUS	7	494	12	10	523
Likely Benign	0	24	90	311	425
Benign	0	3	19	29	51
Conflicting	—				11
Total	20	525	121	350	1,027

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap PLXNA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →