PLEKHG5

Chr 1AR

pleckstrin homology and RhoGEF domain containing G5

Also known as: ARHGEF45, CMTRIC, DSMA4, GEF720, HMNR4, Syx, Tech

NCBI Gene: 57449 ENSG00000171680 UniProt: O94827 OMIM: 611101

The protein activates nuclear factor kappa B (NFKB1) signaling and is located in the cytoplasm. Autosomal recessive mutations cause distal hereditary motor neuronopathy type 4 and recessive intermediate Charcot-Marie-Tooth disease type C through a predicted gain-of-function mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in this gene are associated with autosomal recessive distal spinal muscular atrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, recessive intermediate CMIM #615376

Neuronopathy, distal hereditary motor, autosomal recessive 4MIM #611067

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · neuromuscular disease · AR · ClinGen 2023

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.56

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.56LOEUF

pLI 0.000

Z-score 3.94

OE 0.38 (0.26–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.49Z-score

OE missense 0.84 (0.78–0.90)

552 obs / 659.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.26–0.56)

0≤0.351.4

Missense OE?0.84 (0.78–0.90)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 18 / 47.2Missense obs/exp: 552 / 659.7Syn Z: -0.18

Background carrier burden — how many people carry a rare variant somewhere in PLEKHG5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 31

1,514 rare PASS variants

Rare truncating (LoF)

1 in 500

172 rare PASS variants

Rare synonymous (reference)

1 in 52

682 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PLEKHG5. 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 35	1 in 330
South Asian	~43k	1 in 19	1 in 590
Remaining (unassigned)	~30k	1 in 25	1 in 850
European (Finnish)	~27k	1 in 75	1 in 970
Admixed American	~22k	1 in 30	1 in 460
African / African American	~21k	1 in 29	1 in 340
East Asian	~20k	1 in 38	1 in 770
Ashkenazi Jewish	~13k	1 in 87	≈ 1 in 5,800
Middle Eastern	~2,884	1 in 31	1 in 380

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): 19 of 20 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: all 20.? see exons ↓