Is MFN2 p.Asp446= (c.1338C>T) pathogenic?

MFN2 p.Asp446= (c.1338C>T) is classified Likely benign in MFN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-31). Very rare (popmax 0.00329%, sas); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with MFN2 p.Asp446= (c.1338C>T)?

MFN2 p.Asp446= (c.1338C>T) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is MFN2 p.Asp446= (c.1338C>T) in the general population?

MFN2 p.Asp446= (c.1338C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

MFN2 p.Asp446=

c.1338C>T · rs376300393 · VCV742471

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

Charcot-Marie-Tooth disease type 2

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 -10	GERP -1.6
Overall
CADD	4.828	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,080 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000805% 13/1,614,100 alleles · very rare exomes 11/1,461,872 · genomes 2/152,228 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,360
African / African-American	0.00267%	37,505
Admixed American	0.00167%	60,012
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.000508%	196,669

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.Asp446=
Coding: c.1338C>T
MANE Select: NM_014874
dbSNP: rs376300393
Type: single nucleotide variant
Location: chr1:12004559 (GRCh38)
Gene constraint: LOEUF 0.602 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 3 PDB

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 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
MFN2 p.Arg104Trp Pathogenic ★★ same condition
MFN2 p.Arg259Cys 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-asp446 (accessed [today's date]).

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