Is MFN2 p.Val91Met (c.271G>A) pathogenic?

MFN2 p.Val91Met (c.271G>A) is classified Uncertain significance in MFN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-11). AlphaMissense: ambiguous (0.549); Very rare (popmax 0.0011%, sas); Associated with Charcot-Marie-Tooth disease type 2A2.

What condition is associated with MFN2 p.Val91Met (c.271G>A)?

MFN2 p.Val91Met (c.271G>A) is associated with Charcot-Marie-Tooth disease type 2A2, neuropathy, hereditary motor and sensory, type 6A, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (ClinVar).

How common is MFN2 p.Val91Met (c.271G>A) in the general population?

MFN2 p.Val91Met (c.271G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MFN2 p.Val91Met (c.271G>A)?

AlphaMissense predicts ambiguous (score 0.549) — an in-silico prediction, not a clinical call.

MFN2 p.Val91Met

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.271G>A · rs1557519001 · VCV873748

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.549 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Charcot-Marie-Tooth disease type 2A2

Computational evidence

Protein change
AlphaMissense	0.549	ambiguous
REVEL	0.72	pathogenic-leaning
SaProt	LLR -5.08	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 9,784 bp · p 1.5e-16 · regional, not allelic
Overall
CADD	28.7	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 0.0011% South Asian · 1/91,084 alleles

Overall 0.000124% 2/1,614,220 alleles · very rare exomes 2/1,461,894 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	8.47e-05%	1,180,040

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.Val91Met
Coding: c.271G>A
MANE Select: NM_014874
dbSNP: rs1557519001
Type: single nucleotide variant
Location: chr1:11992650 (GRCh38)
Gene constraint: LOEUF 0.602 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 3 PDB
Residue 91: the 'part of a helix bundle domain, formed by helices from n-terminal and c-terminal regions' region; an α-helix

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

Also linked: neuropathy, hereditary motor and sensory, type 6A Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;Charcot-Marie-Tooth disease type 2 hereditary motor and sensory neuropathy type 6

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

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

MFN2 p.Val91Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MFN2 p.Val91= Likely benign ★ same residue
MFN2 p.Val91fs Pathogenic ★ same residue
MFN2 p.Val91Gly Conflicting classifications of pathogenicity ⚠ 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

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-val91met (accessed [today's date]).

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