Is PRX p.Pro761= (c.2283G>A) pathogenic?

PRX p.Pro761= (c.2283G>A) is classified Conflicting classifications of pathogenicity in PRX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-03-23). Very rare (popmax 0.00223%, eas); Associated with Charcot-Marie-Tooth disease type 4F.

What condition is associated with PRX p.Pro761= (c.2283G>A)?

PRX p.Pro761= (c.2283G>A) is associated with Charcot-Marie-Tooth disease type 4F, Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is PRX p.Pro761= (c.2283G>A) in the general population?

PRX p.Pro761= (c.2283G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Charcot-Marie-Tooth disease type 4F inherited?

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

PRX p.Pro761=

c.2283G>A · rs1340076007 · VCV892698

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Charcot-Marie-Tooth disease type 4F

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 -8.6	GERP -4.5
Overall
CADD	0.081	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,902 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.0013% 21/1,614,058 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00469%	21,333
East Asiangrpmax	0.00223%	44,902
European (non-Finnish)	0.00136%	73,753
African / African-American	0.00133%	74,916

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.Pro761=
Coding: c.2283G>A
MANE Select: NM_181882
dbSNP: rs1340076007
Type: single nucleotide variant
Location: chr19:40396069 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB
Residue 761: the '55 x 5 aa approximate tandem repeats of [lvmag]-[psreqc]-[edkl]-[livmap]-[aqkhrpe]; that may have a tripeptide spacer of [lv]-p-[ker]' region

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

Disease context

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

Also linked: Charcot-Marie-Tooth disease type 4

For Charcot-Marie-Tooth disease type 4F (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

PRX p.Pro761Leu Uncertain significance ★★ ⚠ same residue
PRX p.Pro761Arg Uncertain significance ★ ⚠ same residue
PRX p.Pro761Ser 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

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-pro761 (accessed [today's date]).

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