Is PRX p.Leu306Pro (c.917T>C) pathogenic?

PRX p.Leu306Pro (c.917T>C) is classified Uncertain significance in PRX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-14). AlphaMissense: ambiguous (0.3408); Very rare (popmax 0.00672%, afr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with PRX p.Leu306Pro (c.917T>C)?

PRX p.Leu306Pro (c.917T>C) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is PRX p.Leu306Pro (c.917T>C) in the general population?

PRX p.Leu306Pro (c.917T>C) is very rare (popmax 0.00672%, afr) (gnomAD).

What do computational predictors say about PRX p.Leu306Pro (c.917T>C)?

AlphaMissense predicts ambiguous (score 0.3408) — an in-silico prediction, not a clinical call.

PRX p.Leu306Pro

c.917T>C · rs756803817 · VCV2141184

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3408 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00672%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.3408	ambiguous
REVEL	0.08	moderately benign-leaning
SaProt	LLR -9.09	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 11 kb · p 0.97 · regional, not allelic
Overall
CADD	23.9	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 0.00672% African / African-American · 5/74,414 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000375% 6/1,600,360 alleles · very rare exomes 3/1,448,220 · genomes 3/152,140 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00672%	14,883
European (non-Finnish)	8.51e-05%	1,174,540

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.Leu306Pro
Coding: c.917T>C
MANE Select: NM_181882
dbSNP: rs756803817
Type: single nucleotide variant
Location: chr19:40397435 (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

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-leu306pro (accessed [today's date]).

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