Is MFN2 p.Val705Phe (c.2113G>T) pathogenic?

MFN2 p.Val705Phe (c.2113G>T) is classified Uncertain significance in MFN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-08). AlphaMissense: likely benign (0.133); Very rare (popmax 0.000424%, nfe); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with MFN2 p.Val705Phe (c.2113G>T)?

MFN2 p.Val705Phe (c.2113G>T) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is MFN2 p.Val705Phe (c.2113G>T) in the general population?

MFN2 p.Val705Phe (c.2113G>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about MFN2 p.Val705Phe (c.2113G>T)?

AlphaMissense predicts likely benign (score 0.133) — an in-silico prediction, not a clinical call.

MFN2 p.Val705Phe

c.2113G>T · VCV3661836

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2

Computational evidence

Protein change
AlphaMissense	0.133	likely benign
REVEL	0.651	pathogenic-leaning
SaProt	LLR -7.98	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 -0.39	GERP -3.3
Regional constraint	o/e 0.85	unconstrained · MANE · 13 kb · p 0.00012 · regional, not allelic
Overall
CADD	17.7	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

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,020 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,164 alleles · very rare exomes 5/1,461,876 · genomes 0/152,288 · joint denominator

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: MFN2
Protein: p.Val705Phe
Coding: c.2113G>T
MANE Select: NM_014874
Type: single nucleotide variant
Location: chr1:12009635 (GRCh38)
Gene constraint: LOEUF 0.602 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 3 PDB
Residue 705: a UniProt-annotated variant site (in)

Full MFN2 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

MFN2 p.Val705Ile Benign/Likely benign ★★ same residue
MFN2 p.Val705Asp Uncertain significance ★ ⚠ same residue
MFN2 c.1160+1G>A Likely pathogenic ★★ same condition
MFN2 c.475-1G>C Pathogenic ★★ same condition
MFN2 p.Ala166Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
MFN2 p.Ala220Thr Pathogenic/Likely pathogenic ★★ same condition
MFN2 p.Ala383Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
MFN2 p.Ala738Val 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-val705phe (accessed [today's date]).

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