Is PRX p.Glu682Lys (c.2044G>A) pathogenic?

PRX p.Glu682Lys (c.2044G>A) is classified Conflicting classifications of pathogenicity in PRX (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-26). AlphaMissense: likely benign (0.1254); Very rare (popmax 0.00305%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with PRX p.Glu682Lys (c.2044G>A)?

PRX p.Glu682Lys (c.2044G>A) is associated with Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 3, Charcot-Marie-Tooth disease type 4F (ClinVar).

How common is PRX p.Glu682Lys (c.2044G>A) in the general population?

PRX p.Glu682Lys (c.2044G>A) is very rare (popmax 0.00305%, nfe) (gnomAD).

What do computational predictors say about PRX p.Glu682Lys (c.2044G>A)?

AlphaMissense predicts likely benign (score 0.1254) — an in-silico prediction, not a clinical call.

PRX p.Glu682Lys

c.2044G>A · rs761277865 · VCV698396

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1254 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.1254	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -12.58	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -0.021, phastCons 0.64
Regional constraint	o/e 0.96	unconstrained · MANE · 2,740 bp · p 0.15 · regional, not allelic
Overall
CADD	16.43	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 0.00305% European (non-Finnish) · 36/1,179,458 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00789% 127/1,610,102 alleles · very rare exomes 112/1,461,022 · genomes 15/149,080 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.264%	379
Remaining individualsnot grpmax-eligible	0.0192%	5,197
European (non-Finnish)grpmax	0.00305%	32,763
African / African-American	0.00137%	73,036

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu682Lys
Coding: c.2044G>A
MANE Select: NM_181882
dbSNP: rs761277865
Type: single nucleotide variant
Location: chr19:40396308 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB
Residue 682: 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 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 3 Charcot-Marie-Tooth disease type 4F

Similar variants

PRX p.Glu682Gln Uncertain significance ★ ⚠ same residue
PRX p.Glu682Ter 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
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-glu682lys (accessed [today's date]).

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