Is PRX p.Ala1252= (c.3756C>T) pathogenic?

PRX p.Ala1252= (c.3756C>T) is classified Likely benign in PRX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-18). Very rare (popmax 0.008%, afr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with PRX p.Ala1252= (c.3756C>T)?

PRX p.Ala1252= (c.3756C>T) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is PRX p.Ala1252= (c.3756C>T) in the general population?

PRX p.Ala1252= (c.3756C>T) is very rare (popmax 0.008%, afr) (gnomAD).

PRX p.Ala1252=

c.3756C>T · rs567256423 · VCV1628292

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.008%, afr)

Conditions

Charcot-Marie-Tooth disease type 4

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 -2.5	GERP -2.9
Overall
CADD	0.067	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.008% African / African-American · 6/75,008 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000497% 8/1,608,412 alleles · very rare exomes 5/1,456,198 · genomes 3/152,214 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.008%	12,501
Remaining individualsnot grpmax-eligible	0.0016%	62,390
South Asian	0.0011%	91,008

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.Ala1252=
Coding: c.3756C>T
MANE Select: NM_181882
dbSNP: rs567256423
Type: single nucleotide variant
Location: chr19:40394596 (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

Similar variants

PRX p.Ala1252Thr 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-ala1252 (accessed [today's date]).

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