Is PRX p.Ala1459Val (c.4376C>T) pathogenic?

PRX p.Ala1459Val (c.4376C>T) is classified Uncertain significance in PRX (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-08-23). AlphaMissense: likely benign (0.1205); Ultra-rare (popmax 0.011%, sas); Associated with Charcot-Marie-Tooth disease type 4F.

What condition is associated with PRX p.Ala1459Val (c.4376C>T)?

PRX p.Ala1459Val (c.4376C>T) is associated with Charcot-Marie-Tooth disease type 4F, Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is PRX p.Ala1459Val (c.4376C>T) in the general population?

PRX p.Ala1459Val (c.4376C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

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

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

What do computational predictors say about PRX p.Ala1459Val (c.4376C>T)?

AlphaMissense predicts likely benign (score 0.1205) — an in-silico prediction, not a clinical call.

PRX p.Ala1459Val

c.4376C>T · rs373051724 · VCV329245

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1205 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4F

Computational evidence

Protein change
AlphaMissense	0.1205	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -6.71	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 6.5	GERP 0.62, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,740 bp · p 0.15 · regional, not allelic
Overall
CADD	23.3	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 0.011% South Asian · 10/91,082 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00279% 45/1,612,296 alleles · ultra-rare exomes 36/1,460,120 · genomes 9/152,176 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.00961%	10,407
East Asian	0.00668%	14,967
African / African-American	0.00667%	14,985
Admixed American	0.005%	19,991
European (non-Finnish)	0.00153%	65,545

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.Ala1459Val
Coding: c.4376C>T
MANE Select: NM_181882
dbSNP: rs373051724
Type: single nucleotide variant
Location: chr19:40393976 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB
Residue 1459: the 'disordered' 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

Also linked: Charcot-Marie-Tooth disease type 4

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

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

Similar variants

PRX p.Ala1459= 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
PRX p.Arg464Ter 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-ala1459val (accessed [today's date]).

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