Is PRX p.Pro513Leu (c.1538C>T) pathogenic?

PRX p.Pro513Leu (c.1538C>T) is classified Uncertain significance in PRX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-12). AlphaMissense: likely benign (0.3335); Rare (popmax 0.169%, eas); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with PRX p.Pro513Leu (c.1538C>T)?

PRX p.Pro513Leu (c.1538C>T) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is PRX p.Pro513Leu (c.1538C>T) in the general population?

PRX p.Pro513Leu (c.1538C>T) is rare (popmax 0.169%, eas) (gnomAD).

What do computational predictors say about PRX p.Pro513Leu (c.1538C>T)?

AlphaMissense predicts likely benign (score 0.3335) — an in-silico prediction, not a clinical call.

PRX p.Pro513Leu

c.1538C>T · rs148742209 · VCV570459

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3335 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.169%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.3335	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -12.59	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.1, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 161 bp · p 1.9e-06 · regional, not allelic
Overall
CADD	22.0	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 0.169% East Asian · 76/44,846 alleles

Filtering AF 0.139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.128%

Overall 0.00558% 90/1,613,434 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.169%	590
Remaining individualsnot grpmax-eligible	0.0016%	62,466
Finnishnot grpmax-eligible	0.00156%	63,998
African / African-American	0.00134%	74,844
European (non-Finnish)	0.000932%	107,261

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.Pro513Leu
Coding: c.1538C>T
MANE Select: NM_181882
dbSNP: rs148742209
Type: single nucleotide variant
Location: chr19:40396814 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB
Residue 513: 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 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRX p.Pro513= Benign/Likely benign ★★ 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-pro513leu (accessed [today's date]).

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