Is PLEKHG5 p.Pro28= (c.84G>A) pathogenic?

PLEKHG5 p.Pro28= (c.84G>A) is classified Likely benign in PLEKHG5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). Ultra-rare (popmax 0.0535%, eas); Associated with neuronopathy, distal hereditary motor, autosomal recessive 4.

What condition is associated with PLEKHG5 p.Pro28= (c.84G>A)?

PLEKHG5 p.Pro28= (c.84G>A) is associated with neuronopathy, distal hereditary motor, autosomal recessive 4, Charcot-Marie-Tooth disease recessive intermediate C (ClinVar).

How common is PLEKHG5 p.Pro28= (c.84G>A) in the general population?

PLEKHG5 p.Pro28= (c.84G>A) is ultra-rare (popmax 0.0535%, eas) (gnomAD).

PLEKHG5 p.Pro28=

Q: How is Autosomal recessive lower motor neuron disease with childhood onset inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.84G>A · rs140428005 · VCV681851

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, eas)

Conditions

neuronopathy, distal hereditary motor, autosomal recessive 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -2.8
Overall
CADD	2.705	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0535% East Asian · 24/44,890 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00359% 58/1,613,714 alleles · ultra-rare exomes 51/1,461,330 · genomes 7/152,384 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0535%	1,870
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.008%	12,502
South Asian	0.0022%	45,544
European (non-Finnish)	0.00212%	47,201
African / African-American	0.00133%	75,078

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PLEKHG5
Protein: p.Pro28=
Coding: c.84G>A
MANE Select: NM_020631
dbSNP: rs140428005
Type: single nucleotide variant
Location: chr1:6475996 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.94
Residue 28: the 'disordered' region

Full PLEKHG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronopathy, distal hereditary motor, autosomal recessive 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease recessive intermediate C

For Autosomal recessive lower motor neuron disease with childhood onset (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

PLEKHG5 p.Pro28Leu Uncertain significance ★★ same residue
PLEKHG5 p.Pro28Ser Uncertain significance ★★ ⚠ same residue
PLEKHG5 c.1132-2A>C Pathogenic/Likely pathogenic ★★ same condition
PLEKHG5 c.985-2A>G Pathogenic/Likely pathogenic ★★ same condition
PLEKHG5 p.Arg848Ter Pathogenic/Likely pathogenic ★★ same condition
PLEKHG5 p.Arg930Ter Pathogenic ★★ same condition
PLEKHG5 p.Gln685Ter Pathogenic/Likely pathogenic ★★ same condition
PLEKHG5 p.Glu443Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/plekhg5-p-pro28 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown