Is PRX p.Leu96= (c.286C>T) pathogenic?

PRX p.Leu96= (c.286C>T) is classified Likely benign in PRX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-09). Ultra-rare (popmax 0.033%, mid); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with PRX p.Leu96= (c.286C>T)?

PRX p.Leu96= (c.286C>T) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is PRX p.Leu96= (c.286C>T) in the general population?

PRX p.Leu96= (c.286C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

PRX p.Leu96=

c.286C>T · rs149325913 · VCV699921

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

Charcot-Marie-Tooth disease type 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 7.4	GERP -1.1, phastCons 1
Overall
CADD	13.58	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00223% 36/1,614,104 alleles · ultra-rare exomes 36/1,461,784 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0048%	20,834
European (non-Finnish)	0.00263%	38,063

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: PRX
Protein: p.Leu96=
Coding: c.286C>T
MANE Select: NM_181882
dbSNP: rs149325913
Type: single nucleotide variant
Location: chr19:40398715 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB
Residue 96: the pdz domain; a β-strand

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

Disease context

Charcot-Marie-Tooth disease type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRX p.Leu96Pro Uncertain significance ★ ⚠ same residue
PRX c.184+2T>C Likely pathogenic ★★ same condition
PRX p.Arg1070Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg196Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg364Ter Pathogenic ★★ same condition
PRX p.Arg368Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg392Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg464Ter 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/prx-p-leu96 (accessed [today's date]).

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