Is PRX p.Pro660Arg (c.1979C>G) pathogenic?

PRX p.Pro660Arg (c.1979C>G) is classified Uncertain significance in PRX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-01-11). AlphaMissense: ambiguous (0.397); Very rare (popmax 0.00161%, nfe); Associated with Charcot-Marie-Tooth disease type 3.

What condition is associated with PRX p.Pro660Arg (c.1979C>G)?

PRX p.Pro660Arg (c.1979C>G) is associated with Charcot-Marie-Tooth disease type 3, Charcot-Marie-Tooth disease type 4F, Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is PRX p.Pro660Arg (c.1979C>G) in the general population?

PRX p.Pro660Arg (c.1979C>G) is very rare (popmax 0.00161%, nfe) (gnomAD).

How is Dejerine-Sottas syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PRX p.Pro660Arg (c.1979C>G)?

AlphaMissense predicts ambiguous (score 0.397) — an in-silico prediction, not a clinical call.

PRX p.Pro660Arg

c.1979C>G · rs748737580 · VCV942828

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Charcot-Marie-Tooth disease type 3

Computational evidence

Protein change
AlphaMissense	0.397	ambiguous
REVEL	0.114	moderately benign-leaning
SaProt	LLR -13.13	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.35, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,740 bp · p 0.15 · regional, not allelic
Overall
CADD	18.49	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 0.00161% European (non-Finnish) · 19/1,179,796 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.0013% 21/1,612,920 alleles · very rare exomes 17/1,461,746 · genomes 4/151,174 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,094
Remaining individualsnot grpmax-eligible	0.0016%	62,464
African / African-American	0.00134%	74,498

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.Pro660Arg
Coding: c.1979C>G
MANE Select: NM_181882
dbSNP: rs748737580
Type: single nucleotide variant
Location: chr19:40396373 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB
Residue 660: 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 3 — 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

For Dejerine-Sottas syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

PRX p.Pro660Leu Uncertain significance ★★ ⚠ same residue
PRX p.Pro660= 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

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-pro660arg (accessed [today's date]).

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