Is MFN2 p.Val69Phe (c.205G>T) pathogenic?

MFN2 p.Val69Phe (c.205G>T) is classified Pathogenic in MFN2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2004-05-11). AlphaMissense: likely benign (0.3182); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 2A2.

What condition is associated with MFN2 p.Val69Phe (c.205G>T)?

MFN2 p.Val69Phe (c.205G>T) is associated with Charcot-Marie-Tooth disease type 2A2 (ClinVar).

How common is MFN2 p.Val69Phe (c.205G>T) in the general population?

MFN2 p.Val69Phe (c.205G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MFN2 p.Val69Phe (c.205G>T)?

AlphaMissense predicts likely benign (score 0.3182) — an in-silico prediction, not a clinical call.

MFN2 p.Val69Phe

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.205G>T · rs28940296 · VCV2273

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3182 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2A2

Computational evidence

Protein change
AlphaMissense	0.3182	likely benign ⚠ discordant with ClinVar
REVEL	0.691	pathogenic-leaning
SaProt	LLR -8.71	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.58, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 9,784 bp · p 1.5e-16 · regional, not allelic
Overall
CADD	25.0	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.Val69Phe
Coding: c.205G>T
MANE Select: NM_014874
dbSNP: rs28940296
Type: single nucleotide variant
Location: chr1:11992584 (GRCh38)
Gene constraint: LOEUF 0.602 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 3 PDB
Residue 69: a UniProt-annotated variant site (in cmt2a2a; uncertain significance); the 'part of a helix bundle domain, formed by helices from n-terminal and c-terminal regions' region

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.Val69Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
MFN2 p.Val69= Likely benign ★ 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.Arg280His 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-val69phe (accessed [today's date]).

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