Is MFN2 p.Arg280Pro (c.839G>C) pathogenic?

MFN2 p.Arg280Pro (c.839G>C) is classified Likely pathogenic in MFN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-24). AlphaMissense: likely pathogenic (0.9986); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 2A2.

What condition is associated with MFN2 p.Arg280Pro (c.839G>C)?

MFN2 p.Arg280Pro (c.839G>C) is associated with Charcot-Marie-Tooth disease type 2A2 (ClinVar).

How common is MFN2 p.Arg280Pro (c.839G>C) in the general population?

MFN2 p.Arg280Pro (c.839G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MFN2 p.Arg280Pro (c.839G>C)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

MFN2 p.Arg280Pro

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2A2 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.839G>C · rs28940294 · VCV801444

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2A2

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic ✓ concordant with ClinVar · top 2% in MFN2
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -14.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 13 kb · p 0.00012 · regional, not allelic
Overall
CADD	33.0	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: MFN2
Protein: p.Arg280Pro
Coding: c.839G>C
MANE Select: NM_014874
dbSNP: rs28940294
Type: single nucleotide variant
Location: chr1:12001423 (GRCh38)
Gene constraint: LOEUF 0.602 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 3 PDB
Residue 280: an α-helix; a UniProt-annotated variant site (in cmt2a2a; likely pathogenic); the dynamin-type g domain

Full MFN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 2A2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant Charcot-Marie-Tooth disease type 2A2 (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

MFN2 p.Arg280His Pathogenic/Likely pathogenic ★★ same residue
MFN2 p.Arg280Cys Likely pathogenic ★★ same residue
MFN2 p.Ala166Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
MFN2 p.Ala220Thr Pathogenic/Likely pathogenic ★★ same condition
MFN2 p.Ala738Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
MFN2 p.Arg104Trp Pathogenic ★★ same condition
MFN2 p.Arg259Cys Pathogenic/Likely pathogenic ★★ same condition
MFN2 p.Arg294Ter Pathogenic/Likely pathogenic ★★ 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/mfn2-p-arg280pro (accessed [today's date]).

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