Is MED25 p.Pro78= (c.234C>G) pathogenic?

MED25 p.Pro78= (c.234C>G) is classified Benign in MED25 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Common (popmax 12.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Charcot-Marie-Tooth disease.

What condition is associated with MED25 p.Pro78= (c.234C>G)?

MED25 p.Pro78= (c.234C>G) is associated with Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2 (ClinVar).

MED25 p.Pro78=

Q: How common is MED25 p.Pro78= (c.234C>G) in the general population?

MED25 p.Pro78= (c.234C>G) is common (popmax 12.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.234C>G · rs74863643 · VCV329878

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 12.4%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Charcot-Marie-Tooth disease

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 -8.7	GERP -3.2
Overall
CADD	1.831	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.4% East Asian · 5,569/44,888 alleles

Filtering AF 12.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 12%

Overall 1.32% 21,302/1,614,180 alleles · common exomes 15,822/1,461,832 · genomes 5,480/152,348 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	12.4%	8
African / African-American	7.9%	13
Admixed American	7.64%	13
South Asian	2.42%	41
Remaining individualsnot grpmax-eligible	2.13%	47
Middle Eastern	0.726%	138
Ashkenazi Jewishnot grpmax-eligible	0.429%	233
European (non-Finnish)	0.128%	784
Finnishnot grpmax-eligible	0.00625%	16,009

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.Pro78=
Coding: c.234C>G
MANE Select: NM_030973
dbSNP: rs74863643
Type: single nucleotide variant
Location: chr19:49819225 (GRCh38)
Gene constraint: LOEUF 0.874 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.18 · 10 PDB
Residue 78: the 'interaction with the mediator complex' region

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

Disease context

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

Also linked: Charcot-Marie-Tooth disease type 2

Similar variants

MED25 p.Pro78Ala 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-pro78 (accessed [today's date]).

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