Is PRX p.Pro351Ser (c.1051C>T) pathogenic?

PRX p.Pro351Ser (c.1051C>T) is classified Benign in PRX (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1759); Common (popmax 6.68%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Charcot-Marie-Tooth disease.

What condition is associated with PRX p.Pro351Ser (c.1051C>T)?

PRX p.Pro351Ser (c.1051C>T) is associated with Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 4F, Charcot-Marie-Tooth disease type 4 (ClinVar).

What do computational predictors say about PRX p.Pro351Ser (c.1051C>T)?

AlphaMissense predicts likely benign (score 0.1759) — an in-silico prediction, not a clinical call.

PRX p.Pro351Ser

Q: How common is PRX p.Pro351Ser (c.1051C>T) in the general population?

PRX p.Pro351Ser (c.1051C>T) is common (popmax 6.68%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1051C>T · rs73933276 · VCV220690

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1759 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.68%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease

Computational evidence

Protein change
AlphaMissense	0.1759	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -7.90	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 8.6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 11 kb · p 0.97 · regional, not allelic
Overall
CADD	24.9	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 6.68% African / African-American · 5,012/75,002 alleles

Filtering AF 6.53% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.46%

Overall 0.37% 5,966/1,613,266 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.68%	15
Admixed American	0.513%	195
Remaining individualsnot grpmax-eligible	0.451%	222
Middle Eastern	0.297%	337
European (non-Finnish)	0.0284%	3,522
South Asian	0.011%	9,108
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Pro351Ser
Coding: c.1051C>T
MANE Select: NM_181882
dbSNP: rs73933276
Type: single nucleotide variant
Location: chr19:40397301 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

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
PRX p.Arg897Ter 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-pro351ser (accessed [today's date]).

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