Is MED25 p.Pro653= (c.1959A>G) pathogenic?

MED25 p.Pro653= (c.1959A>G) is classified Likely benign in MED25 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-15). Very rare (popmax 0.000424%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with MED25 p.Pro653= (c.1959A>G)?

MED25 p.Pro653= (c.1959A>G) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is MED25 p.Pro653= (c.1959A>G) in the general population?

MED25 p.Pro653= (c.1959A>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

MED25 p.Pro653=

c.1959A>G · rs757384751 · VCV703248

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000424%, 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.
REVEL	0.036	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8	GERP -3.1
Overall
CADD	0.78	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,718 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,612,002 alleles · very rare exomes 3/1,460,572 · genomes 2/151,430 · joint denominator

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.Pro653=
Coding: c.1959A>G
MANE Select: NM_030973
dbSNP: rs757384751
Type: single nucleotide variant
Location: chr19:49835939 (GRCh38)
Gene constraint: LOEUF 0.874 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.18 · 10 PDB
Residue 653: 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

Similar variants

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
MED25 p.Ala364Thr Uncertain significance ★★ ⚠ same condition
MED25 p.Ala401Val 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-pro653 (accessed [today's date]).

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