Is PRX p.Leu623= (c.1869T>G) pathogenic?

PRX p.Leu623= (c.1869T>G) is classified Uncertain significance in PRX (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0194%, afr); Associated with Charcot-Marie-Tooth disease type 4F.

What condition is associated with PRX p.Leu623= (c.1869T>G)?

PRX p.Leu623= (c.1869T>G) is associated with Charcot-Marie-Tooth disease type 4F (ClinVar).

How common is PRX p.Leu623= (c.1869T>G) in the general population?

PRX p.Leu623= (c.1869T>G) is ultra-rare (popmax 0.0194%, afr) (gnomAD).

How is Charcot-Marie-Tooth disease type 4F inherited?

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

PRX p.Leu623=

c.1869T>G · rs1241434904 · VCV893495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0194%, afr)

Conditions

Charcot-Marie-Tooth disease type 4F

Computational evidence

Protein change
Missense predictors do not apply to this variant type.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Overall
CADD	0.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0194% African / African-American · 11/56,732 alleles

Filtering AF 0.0109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00836%

Overall 0.00176% 27/1,533,166 alleles · ultra-rare exomes 0/1,438,064 · genomes 27/95,102 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0194%	5,157
Ashkenazi Jewishnot grpmax-eligible	0.00369%	27,072
Finnishnot grpmax-eligible	0.00169%	59,056
European (non-Finnish)	0.00114%	87,812
South Asian	0.00113%	88,480

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.Leu623=
Coding: c.1869T>G
MANE Select: NM_181882
dbSNP: rs1241434904
Type: single nucleotide variant
Location: chr19:40396483 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB
Residue 623: 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 4F — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Charcot-Marie-Tooth disease type 4F (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

PRX p.Leu623Arg Uncertain significance ★★ ⚠ same residue
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.Arg464Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg897Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg953Ter 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-leu623 (accessed [today's date]).

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