Is PRX p.Pro363Ala (c.1087C>G) pathogenic?

PRX p.Pro363Ala (c.1087C>G) is classified Uncertain significance in PRX (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely pathogenic (0.7402); Very rare (popmax 0.00133%, afr); Associated with Charcot-Marie-Tooth disease type 4F.

What condition is associated with PRX p.Pro363Ala (c.1087C>G)?

PRX p.Pro363Ala (c.1087C>G) is associated with Charcot-Marie-Tooth disease type 4F (ClinVar).

How common is PRX p.Pro363Ala (c.1087C>G) in the general population?

PRX p.Pro363Ala (c.1087C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

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

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

What do computational predictors say about PRX p.Pro363Ala (c.1087C>G)?

AlphaMissense predicts likely pathogenic (score 0.7402) — an in-silico prediction, not a clinical call.

PRX p.Pro363Ala

c.1087C>G · rs886054439 · VCV329278

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7402 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4F

Computational evidence

Protein change
AlphaMissense	0.7402	likely pathogenic · top 6% in PRX
REVEL	0.16	moderately benign-leaning
SaProt	LLR -10.84	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 11 kb · p 0.97 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,942 alleles

Overall 6.2e-05% 1/1,613,600 alleles · very rare exomes 0/1,461,386 · genomes 1/152,214 · joint denominator

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.Pro363Ala
Coding: c.1087C>G
MANE Select: NM_181882
dbSNP: rs886054439
Type: single nucleotide variant
Location: chr19:40397265 (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 4F — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

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

Similar variants

PRX p.Pro363Leu Uncertain significance ★ ⚠ same residue
PRX p.Pro363Ser Uncertain significance ★ ⚠ same residue
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.Arg464Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg897Ter 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-pro363ala (accessed [today's date]).

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