Is PRX p.Ser560Pro (c.1678T>C) pathogenic?

PRX p.Ser560Pro (c.1678T>C) is classified Uncertain significance in PRX (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0551); Ultra-rare (popmax 0.0371%, afr); Associated with Charcot-Marie-Tooth disease.

What condition is associated with PRX p.Ser560Pro (c.1678T>C)?

PRX p.Ser560Pro (c.1678T>C) is associated with Charcot-Marie-Tooth disease (ClinVar).

How common is PRX p.Ser560Pro (c.1678T>C) in the general population?

PRX p.Ser560Pro (c.1678T>C) is ultra-rare (popmax 0.0371%, afr) (gnomAD).

What do computational predictors say about PRX p.Ser560Pro (c.1678T>C)?

AlphaMissense predicts likely benign (score 0.0551) — an in-silico prediction, not a clinical call.

PRX p.Ser560Pro

c.1678T>C · rs1299743311 · VCV916909

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0551 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0371%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.0551	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -6.38	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 1.7	GERP -2.9, phastCons 0.91
Regional constraint	o/e 0.96	unconstrained · MANE · 2,740 bp · p 0.15 · regional, not allelic
Overall
CADD	0.114	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 0.0371% African / African-American · 24/64,664 alleles

Filtering AF 0.0255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0217%

Overall 0.00316% 50/1,582,040 alleles · ultra-rare exomes 0/1,461,070 · genomes 50/120,970 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0371%	2,694
Admixed American	0.00702%	14,254
East Asian	0.0046%	21,761
South Asian	0.00445%	22,486
Finnishnot grpmax-eligible	0.00329%	30,420
Remaining individualsnot grpmax-eligible	0.00161%	62,060
European (non-Finnish)	0.00111%	89,879

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.Ser560Pro
Coding: c.1678T>C
MANE Select: NM_181882
dbSNP: rs1299743311
Type: single nucleotide variant
Location: chr19:40396674 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB
Residue 560: 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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRX p.Ser560= Likely benign ★★ same residue
PRX p.Arg196Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg364Ter Pathogenic ★★ same condition
PRX p.Arg953Ter Pathogenic ★★ same condition
PRX p.Cys715Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Gln622Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Glu197Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Ala1000Val Uncertain significance ★★ ⚠ 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-ser560pro (accessed [today's date]).

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