Is PRX p.Arg215fs (c.642dup) pathogenic?

PRX p.Arg215fs (c.642dup) is classified Pathogenic in PRX (ClinVar, Single submitter, 2 submitters; last evaluated 2021-07-13). Very rare (popmax 0.00189%, amr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with PRX p.Arg215fs (c.642dup)?

PRX p.Arg215fs (c.642dup) is associated with Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease (ClinVar).

How common is PRX p.Arg215fs (c.642dup) in the general population?

PRX p.Arg215fs (c.642dup) is very rare (popmax 0.00189%, amr) (gnomAD).

PRX p.Arg215fs

c.642dup · rs768074428 · VCV637943

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00189%, amr)

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (7 of 7) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.1	GERP 1.3, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00189% Admixed American · 1/52,798 alleles

Overall 0.000192% 3/1,562,086 alleles · very rare exomes 3/1,409,776 · genomes 0/152,310 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00194%	51,638
Admixed Americangrpmax	0.00189%	52,798
European (non-Finnish)	8.64e-05%	1,158,048

Finnish 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: PRX
Protein: p.Arg215fs
Coding: c.642dup
MANE Select: NM_181882
dbSNP: rs768074428
Type: Duplication
Location: chr19:40397709 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB

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

Also linked: Charcot-Marie-Tooth disease

Similar variants

PRX p.Gln60fs Pathogenic/Likely pathogenic ★★ same condition
PRX p.Gly952fs Pathogenic/Likely pathogenic ★★ same condition
PRX p.469ELPKVSEMKLPKVPEMAVPEVRLPEV[3] Uncertain significance ★★ same condition
PRX p.Ala1367fs Uncertain significance ★★ same condition
PRX p.Lys529_Met536dup Uncertain significance ★★ same condition
PRX p.Ser259fs Pathogenic ★ same condition
PRX p.Glu677_Pro738dup Uncertain significance ★ same condition
PRX p.Leu523_Leu548dup Uncertain significance ★ 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-arg215fs (accessed [today's date]).

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