Is PRX p.Pro663Ser (c.1987C>T) pathogenic?

PRX p.Pro663Ser (c.1987C>T) is classified Conflicting classifications of pathogenicity in PRX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-08-26). AlphaMissense: likely benign (0.0674); Ultra-rare (popmax 0.06%, afr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with PRX p.Pro663Ser (c.1987C>T)?

PRX p.Pro663Ser (c.1987C>T) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is PRX p.Pro663Ser (c.1987C>T) in the general population?

PRX p.Pro663Ser (c.1987C>T) is ultra-rare (popmax 0.06%, afr) (gnomAD).

What do computational predictors say about PRX p.Pro663Ser (c.1987C>T)?

AlphaMissense predicts likely benign (score 0.0674) — an in-silico prediction, not a clinical call.

PRX p.Pro663Ser

c.1987C>T · rs149183991 · VCV1001735

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0674 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.0674	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -5.49	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 -4.5	GERP -3.1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,740 bp · p 0.15 · regional, not allelic
Overall
CADD	0.013	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 0.06% African / African-American · 41/68,390 alleles

Filtering AF 0.0454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0402%

Overall 0.0027% 43/1,592,302 alleles · ultra-rare exomes 19/1,457,526 · genomes 24/134,776 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.06%	1,668
Remaining individualsnot grpmax-eligible	0.00323%	30,935

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.Pro663Ser
Coding: c.1987C>T
MANE Select: NM_181882
dbSNP: rs149183991
Type: single nucleotide variant
Location: chr19:40396365 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB
Residue 663: 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 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-pro663ser (accessed [today's date]).

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