Is MED25 p.Val596= (c.1788A>G) pathogenic?

MED25 p.Val596= (c.1788A>G) is classified Likely benign in MED25 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-10). Very rare (popmax 0.00187%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with MED25 p.Val596= (c.1788A>G)?

MED25 p.Val596= (c.1788A>G) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is MED25 p.Val596= (c.1788A>G) in the general population?

MED25 p.Val596= (c.1788A>G) is very rare (popmax 0.00187%, nfe) (gnomAD).

MED25 p.Val596=

c.1788A>G · rs1185106322 · VCV2201606

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00187%, 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 4.3	GERP -0.88, phastCons 1
Overall
CADD	7.174	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00187% European (non-Finnish) · 22/1,177,754 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00596% 96/1,609,398 alleles · very rare exomes 85/1,457,420 · genomes 11/151,978 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.104%	963
Remaining individualsnot grpmax-eligible	0.0145%	6,918
European (non-Finnish)grpmax	0.00187%	53,534

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val596=
Coding: c.1788A>G
MANE Select: NM_030973
dbSNP: rs1185106322
Type: single nucleotide variant
Location: chr19:49835768 (GRCh38)
Gene constraint: LOEUF 0.874 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.18 · 10 PDB
Residue 596: 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.Val596Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
MED25 p.Val596Leu 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-val596 (accessed [today's date]).

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