Is PRX p.Ala1268Pro (c.3802G>C) pathogenic?

PRX p.Ala1268Pro (c.3802G>C) is classified Conflicting classifications of pathogenicity in PRX (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.0925); Low-frequency (popmax 1.13%, afr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with PRX p.Ala1268Pro (c.3802G>C)?

PRX p.Ala1268Pro (c.3802G>C) is associated with Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 4F, Charcot-Marie-Tooth disease (ClinVar).

How common is PRX p.Ala1268Pro (c.3802G>C) in the general population?

PRX p.Ala1268Pro (c.3802G>C) is low-frequency (popmax 1.13%, afr) (gnomAD).

What do computational predictors say about PRX p.Ala1268Pro (c.3802G>C)?

AlphaMissense predicts likely benign (score 0.0925) — an in-silico prediction, not a clinical call.

PRX p.Ala1268Pro

c.3802G>C · rs146061247 · VCV382637

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0925 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.13%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.0925	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -6.88	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 0.015	GERP -2
Regional constraint	o/e 0.96	unconstrained · MANE · 2,740 bp · p 0.15 · regional, not allelic
Overall
CADD	15.74	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 1.13% African / African-American · 848/74,842 alleles

Filtering AF 1.07% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.04%

Overall 0.0607% 976/1,606,650 alleles · low-frequency exomes 502/1,454,380 · genomes 474/152,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.13%	88
Remaining individualsnot grpmax-eligible	0.103%	972
Admixed American	0.0709%	1,411
Middle Eastern	0.0331%	3,023
South Asian	0.00443%	22,590
European (non-Finnish)	0.00136%	73,593

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.Ala1268Pro
Coding: c.3802G>C
MANE Select: NM_181882
dbSNP: rs146061247
Type: single nucleotide variant
Location: chr19:40394550 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB

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 4F Charcot-Marie-Tooth disease

Similar variants

PRX p.Ala1268= Likely benign ★★ same residue
PRX p.Ala1268Thr 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-ala1268pro (accessed [today's date]).

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