Is MFN2 p.Ile577= (c.1731C>T) pathogenic?

MFN2 p.Ile577= (c.1731C>T) is classified Likely benign in MFN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-05). Very rare (popmax 0.00267%, afr); Associated with Charcot-Marie-Tooth disease type 2.

What condition is associated with MFN2 p.Ile577= (c.1731C>T)?

MFN2 p.Ile577= (c.1731C>T) is associated with Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is MFN2 p.Ile577= (c.1731C>T) in the general population?

MFN2 p.Ile577= (c.1731C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

MFN2 p.Ile577=

c.1731C>T · VCV3625661

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.43	GERP -3, phastCons 0.028
Overall
CADD	4.531	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,938 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,614,102 alleles · very rare exomes 2/1,461,864 · genomes 1/152,238 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,469
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Ile577=
Coding: c.1731C>T
MANE Select: NM_014874
Type: single nucleotide variant
Location: chr1:12006552 (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 p.Ile577Val 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
MFN2 p.Arg104Trp 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-ile577 (accessed [today's date]).

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