Is PLEKHG5 p.Ser855= (c.2565G>A) pathogenic?

PLEKHG5 p.Ser855= (c.2565G>A) is classified Likely benign in PLEKHG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). Very rare (popmax 0.00224%, eas); Associated with neuronopathy, distal hereditary motor, autosomal recessive 4.

What condition is associated with PLEKHG5 p.Ser855= (c.2565G>A)?

PLEKHG5 p.Ser855= (c.2565G>A) is associated with neuronopathy, distal hereditary motor, autosomal recessive 4, Charcot-Marie-Tooth disease recessive intermediate C (ClinVar).

How common is PLEKHG5 p.Ser855= (c.2565G>A) in the general population?

PLEKHG5 p.Ser855= (c.2565G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

PLEKHG5 p.Ser855=

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.2565G>A · rs372308060 · VCV1102412

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00224%, 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 -20	GERP -3
Overall
CADD	0.263	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,648 alleles

Filtering AF 0.000617% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000476%

Overall 0.00118% 19/1,605,982 alleles · very rare exomes 19/1,454,070 · genomes 0/151,912 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00483%	20,707
East Asiangrpmax	0.00224%	44,648
South Asian	0.00221%	45,274
European (non-Finnish)	0.00111%	90,409

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser855=
Coding: c.2565G>A
MANE Select: NM_020631
dbSNP: rs372308060
Type: single nucleotide variant
Location: chr1:6468271 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.94
Residue 855: 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.Ser855Leu 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
PLEKHG5 p.Glu580Ter 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-ser855 (accessed [today's date]).

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