Is PRX p.Pro1083Arg (c.3248C>G) pathogenic?

PRX p.Pro1083Arg (c.3248C>G) is classified Benign/Likely benign in PRX (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0739); Common (popmax 19.1%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Charcot-Marie-Tooth disease.

What condition is associated with PRX p.Pro1083Arg (c.3248C>G)?

PRX p.Pro1083Arg (c.3248C>G) is associated with Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 4F, Charcot-Marie-Tooth disease type 4 (ClinVar).

What do computational predictors say about PRX p.Pro1083Arg (c.3248C>G)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

PRX p.Pro1083Arg

Q: How common is PRX p.Pro1083Arg (c.3248C>G) in the general population?

PRX p.Pro1083Arg (c.3248C>G) is common (popmax 19.1%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3248C>G · rs3745202 · VCV130052

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 19.1%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.8	GERP 0.63, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,740 bp · p 0.15 · regional, not allelic
Overall
CADD	14.87	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 19.1% European (non-Finnish) · 225,026/1,179,946 alleles

Filtering AF 19% ClinGen BA1/BS1 input FAF95, joint · FAF99 19%

Overall 16.8% 271,469/1,613,640 alleles · common exomes 252,568/1,461,572 · genomes 18,901/152,068 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	19.1%	5
Amishnot grpmax-eligible	18.9%	5
South Asian	16.8%	6
Remaining individualsnot grpmax-eligible	15.7%	6
Finnishnot grpmax-eligible	14.3%	7
Middle Eastern	10.7%	9
Ashkenazi Jewishnot grpmax-eligible	9.87%	10
Admixed American	7.77%	13
African / African-American	3.71%	27
East Asian	2.38%	42

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.Pro1083Arg
Coding: c.3248C>G
MANE Select: NM_181882
dbSNP: rs3745202
Type: single nucleotide variant
Location: chr19:40395104 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB
Residue 1083: a UniProt-annotated variant site (in)

Full PRX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 4F Charcot-Marie-Tooth disease type 4

Similar variants

PRX p.Pro1083Leu Uncertain significance ★★ ⚠ same residue
PRX p.Pro1083= Likely benign ★ same residue
PRX p.Pro1083Trp Uncertain significance ★ same residue
PRX p.Pro1083Ser Uncertain significance ★ ⚠ 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

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-pro1083arg (accessed [today's date]).

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