Is PLEKHG5 p.Ala577= (c.1731C>T) pathogenic?

PLEKHG5 p.Ala577= (c.1731C>T) is classified Likely benign in PLEKHG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-26). Very rare (popmax 0.00801%, afr); Associated with neuronopathy, distal hereditary motor, autosomal recessive 4.

What condition is associated with PLEKHG5 p.Ala577= (c.1731C>T)?

PLEKHG5 p.Ala577= (c.1731C>T) is associated with neuronopathy, distal hereditary motor, autosomal recessive 4, Charcot-Marie-Tooth disease recessive intermediate C (ClinVar).

How common is PLEKHG5 p.Ala577= (c.1731C>T) in the general population?

PLEKHG5 p.Ala577= (c.1731C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

PLEKHG5 p.Ala577=

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.1731C>T · rs138441206 · VCV1556771

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.6	GERP -0.44, phastCons 1
Overall
CADD	7.218	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,920 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000805% 13/1,613,936 alleles · very rare exomes 10/1,461,752 · genomes 3/152,184 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,487
European (non-Finnish)	0.000593%	168,572

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.Ala577=
Coding: c.1731C>T
MANE Select: NM_020631
dbSNP: rs138441206
Type: single nucleotide variant
Location: chr1:6470305 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.94

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.Ala577Thr Uncertain significance ★★ ⚠ same residue
PLEKHG5 p.Ala577fs Pathogenic ★ 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-ala577 (accessed [today's date]).

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