PLXND1

Chr 3AR

plexin D1

Also known as: CHTD9, PLEXD1

NCBI Gene: 23129 ENSG00000004399 UniProt: Q9Y4D7 OMIM: 604282

PLXND1 encodes a cell surface receptor for semaphorins that regulates cell migration, synapse formation, and cardiovascular development. Mutations cause autosomal recessive congenital heart defects with multiple cardiac malformations. This gene is highly constrained against loss-of-function variants, indicating it is essential for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables protein domain specific binding activity. Predicted to be involved in several processes, including positive regulation of axonogenesis; semaphorin-plexin signaling pathway; and synapse assembly. Predicted to act upstream of or within circulatory system development; dichotomous subdivision of terminal units involved in salivary gland branching; and kidney development. Located in lamellipodium. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Congenital heart defects, multiple types, 9MIM #620294

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Congenital heart defects, multiple types; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.16

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 7.78

OE 0.08 (0.05–0.16)

Highly constrained

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

Missense Constraint?

3.35Z-score

OE missense 0.72 (0.68–0.76)

821 obs / 1138.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.08 (0.05–0.16)

0≤0.351.4

Missense OE?0.72 (0.68–0.76)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 7 / 83.9Missense obs/exp: 821 / 1138.8Syn Z: 0.12

Background carrier burden — how many people carry a rare variant somewhere in PLXND1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 22

2,308 rare PASS variants

Rare truncating (LoF)

1 in 1,900

156 rare PASS variants

Rare synonymous (reference)

1 in 39

1,254 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PLXND1. 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 32	1 in 1,800
South Asian	~43k	1 in 19	1 in 4,100
Remaining (unassigned)	~30k	1 in 18	1 in 2,300
European (Finnish)	~27k	1 in 53	1 in 960
Admixed American	~22k	1 in 20	1 in 4,300
African / African American	~21k	1 in 19	1 in 2,400
East Asian	~20k	1 in 19	1 in 3,800
Ashkenazi Jewish	~13k	1 in 130	1 in 1,800
Middle Eastern	~2,884	1 in 21	≈ 1 in 1,900

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): 32 of 36 coding exons well covered in gnomAD exomes; exons 1, 9, 20, 30 marginal. Genomes: all 36.? see exons ↓