Is MED25 p.Pro682= (c.2046G>A) pathogenic?

MED25 p.Pro682= (c.2046G>A) is classified Likely benign in MED25 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-18). Ultra-rare (popmax 0.0253%, sas); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with MED25 p.Pro682= (c.2046G>A)?

MED25 p.Pro682= (c.2046G>A) is associated with Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease (ClinVar).

How common is MED25 p.Pro682= (c.2046G>A) in the general population?

MED25 p.Pro682= (c.2046G>A) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

MED25 p.Pro682=

c.2046G>A · rs755620011 · VCV697114

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

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	0.033	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.1
Overall
CADD	0.282	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0253% South Asian · 23/90,830 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00621% 100/1,611,042 alleles · ultra-rare exomes 94/1,458,970 · genomes 6/152,072 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,949
Remaining individualsnot grpmax-eligible	0.00963%	10,385
Admixed American	0.00668%	14,966
European (non-Finnish)	0.00509%	19,653
East Asian	0.00446%	22,405
African / African-American	0.00401%	24,955
Finnishnot grpmax-eligible	0.00319%	31,327

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.Pro682=
Coding: c.2046G>A
MANE Select: NM_030973
dbSNP: rs755620011
Type: single nucleotide variant
Location: chr19:49836306 (GRCh38)
Gene constraint: LOEUF 0.874 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.18 · 10 PDB
Residue 682: 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.Pro682Leu 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
MED25 p.Ala364Thr 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-pro682 (accessed [today's date]).

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