Is MED25 p.Pro588= (c.1764G>A) pathogenic?

MED25 p.Pro588= (c.1764G>A) is classified Likely benign in MED25 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-27). Very rare (popmax 0.00577%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with MED25 p.Pro588= (c.1764G>A)?

MED25 p.Pro588= (c.1764G>A) is associated with Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease (ClinVar).

How common is MED25 p.Pro588= (c.1764G>A) in the general population?

MED25 p.Pro588= (c.1764G>A) is very rare (popmax 0.00577%, nfe) (gnomAD).

MED25 p.Pro588=

c.1764G>A · rs758729127 · VCV917048

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00577%, nfe)

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.4
Overall
CADD	0.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00577% European (non-Finnish) · 68/1,178,702 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00423%

Overall 0.00447% 72/1,610,224 alleles · very rare exomes 67/1,457,966 · genomes 5/152,258 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00577%	17,334
East Asian	0.00224%	44,726
Admixed American	0.00167%	59,910
African / African-American	0.00133%	74,912
South Asian	0.0011%	90,688

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: MED25
Protein: p.Pro588=
Coding: c.1764G>A
MANE Select: NM_030973
dbSNP: rs758729127
Type: single nucleotide variant
Location: chr19:49835744 (GRCh38)
Gene constraint: LOEUF 0.874 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.18 · 10 PDB
Residue 588: the 'disordered' region; the 'interaction with rara' region

Full MED25 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease

Similar variants

MED25 p.Pro588Leu Uncertain significance ★ ⚠ same residue
MED25 p.Pro588Ser Uncertain significance ★ ⚠ same residue
MED25 p.Arg140Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
MED25 c.1101+4G>A Uncertain significance ★★ same condition
MED25 c.135-3C>T Uncertain significance ★★ same condition
MED25 p.Ala190Val Uncertain significance ★★ same condition
MED25 p.Ala251Thr Uncertain significance ★★ ⚠ same condition
MED25 p.Ala255Gly Uncertain significance ★★ ⚠ 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/med25-p-pro588 (accessed [today's date]).

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