Is MED25 p.Phe57Ser (c.170T>C) pathogenic?

MED25 p.Phe57Ser (c.170T>C) is classified Uncertain significance in MED25 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: likely pathogenic (0.9981); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with MED25 p.Phe57Ser (c.170T>C)?

MED25 p.Phe57Ser (c.170T>C) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is MED25 p.Phe57Ser (c.170T>C) in the general population?

MED25 p.Phe57Ser (c.170T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MED25 p.Phe57Ser (c.170T>C)?

AlphaMissense predicts likely pathogenic (score 0.9981) — an in-silico prediction, not a clinical call.

MED25 p.Phe57Ser

c.170T>C · rs2073956256 · VCV853370

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9981 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.9981	likely pathogenic · top 8% in MED25
REVEL	0.7	pathogenic-leaning
SaProt	LLR -5.53	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.3, phastCons 1
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MED25
Protein: p.Phe57Ser
Coding: c.170T>C
MANE Select: NM_030973
dbSNP: rs2073956256
Type: single nucleotide variant
Location: chr19:49818606 (GRCh38)
Gene constraint: LOEUF 0.874 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.18 · 10 PDB
Residue 57: 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 type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MED25 p.Phe57Cys 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-phe57ser (accessed [today's date]).

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