Is PRX p.Val546= (c.1638A>G) pathogenic?

PRX p.Val546= (c.1638A>G) is classified Likely benign in PRX (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.00446%, afr); Associated with Charcot-Marie-Tooth disease.

What condition is associated with PRX p.Val546= (c.1638A>G)?

PRX p.Val546= (c.1638A>G) is associated with Charcot-Marie-Tooth disease (ClinVar).

How common is PRX p.Val546= (c.1638A>G) in the general population?

PRX p.Val546= (c.1638A>G) is very rare (popmax 0.00446%, afr) (gnomAD).

PRX p.Val546=

c.1638A>G · rs774541568 · VCV916830

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00446%, afr)

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.3	GERP -2.6
Overall
CADD	0.579	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% African / African-American · 3/67,330 alleles

Filtering AF 0.00118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000628%

Overall 0.000629% 10/1,590,284 alleles · very rare exomes 1/1,459,880 · genomes 9/130,404 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.148%	676
African / African-Americangrpmax	0.00446%	22,443
East Asian	0.0023%	43,554
Admixed American	0.00173%	57,958
Finnishnot grpmax-eligible	0.00161%	62,260
European (non-Finnish)	0.000256%	390,459

Amish 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.Val546=
Coding: c.1638A>G
MANE Select: NM_181882
dbSNP: rs774541568
Type: single nucleotide variant
Location: chr19:40396714 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB
Residue 546: 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.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
PRX p.Ala1091Thr 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-val546 (accessed [today's date]).

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