Is PRX p.Pro487Leu (c.1460C>T) pathogenic?

PRX p.Pro487Leu (c.1460C>T) is classified Uncertain significance in PRX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-28). AlphaMissense: ambiguous (0.4103); Very rare (popmax 0.00667%, amr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with PRX p.Pro487Leu (c.1460C>T)?

PRX p.Pro487Leu (c.1460C>T) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is PRX p.Pro487Leu (c.1460C>T) in the general population?

PRX p.Pro487Leu (c.1460C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about PRX p.Pro487Leu (c.1460C>T)?

AlphaMissense predicts ambiguous (score 0.4103) — an in-silico prediction, not a clinical call.

PRX p.Pro487Leu

c.1460C>T · rs778936443 · VCV569894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4103 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.4103	ambiguous
REVEL	0.182	moderately benign-leaning
SaProt	LLR -12.65	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 11 kb · p 0.97 · regional, not allelic
Overall
CADD	23.8	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 0.00667% Admixed American · 4/59,996 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000929% 15/1,614,024 alleles · very rare exomes 10/1,461,824 · genomes 5/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
South Asian	0.00439%	22,771
East Asian	0.00223%	44,892
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,926
European (non-Finnish)	0.000339%	295,001

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.Pro487Leu
Coding: c.1460C>T
MANE Select: NM_181882
dbSNP: rs778936443
Type: single nucleotide variant
Location: chr19:40396892 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB
Residue 487: 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.Pro487= 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-pro487leu (accessed [today's date]).

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