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

Contributes to semaphorin receptor activity. Involved in T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell and semaphorin-plexin signaling pathway. Located in extracellular exosome. Is active in plasma membrane. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Dworschak-Punetha neurodevelopmental syndromeMIM #619955

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Dworschak-Punetha neurodevelopmental syndrome; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.26

LOEUF· LoF intol.

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in PLXNA1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 30

2,240 rare PASS variants

Rare truncating (LoF)

1 in 1,900

175 rare PASS variants

Rare synonymous (reference)

1 in 27

1,215 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PLXNA1. 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 38	1 in 1,900
South Asian	~43k	1 in 27	1 in 920
Remaining (unassigned)	~30k	1 in 24	1 in 4,300
European (Finnish)	~27k	1 in 74	1 in 2,000
Admixed American	~22k	1 in 25	1 in 3,800
African / African American	~21k	1 in 26	1 in 2,100
East Asian	~20k	1 in 32	1 in 2,000
Ashkenazi Jewish	~13k	1 in 87	1 in 2,100
Middle Eastern	~2,884	1 in 29	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 31 coding exons well covered in gnomAD exomes and genomes.? see exons ↓