Is PRX p.Pro254Leu (c.761C>T) pathogenic?

PRX p.Pro254Leu (c.761C>T) is classified Uncertain significance in PRX (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-24). AlphaMissense: likely benign (0.1107); Very rare (popmax 0.00105%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with PRX p.Pro254Leu (c.761C>T)?

PRX p.Pro254Leu (c.761C>T) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is PRX p.Pro254Leu (c.761C>T) in the general population?

PRX p.Pro254Leu (c.761C>T) is very rare (popmax 0.00105%, nfe) (gnomAD).

What do computational predictors say about PRX p.Pro254Leu (c.761C>T)?

AlphaMissense predicts likely benign (score 0.1107) — an in-silico prediction, not a clinical call.

PRX p.Pro254Leu

c.761C>T · rs748153822 · VCV1010445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1107 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00105%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.1107	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -7.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 1.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 11 kb · p 0.97 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00105% European (non-Finnish) · 12/1,148,318 alleles

Filtering AF 0.000557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00044%

Overall 0.000778% 12/1,542,266 alleles · very rare exomes 12/1,389,914 · genomes 0/152,352 · 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.Pro254Leu
Coding: c.761C>T
MANE Select: NM_181882
dbSNP: rs748153822
Type: single nucleotide variant
Location: chr19:40397591 (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.Pro254= 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-pro254leu (accessed [today's date]).

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