Is MFN2 p.Val136= (c.408A>T) pathogenic?

MFN2 p.Val136= (c.408A>T) is classified Benign/Likely benign in MFN2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-02). Low-frequency (popmax 3.64%, eas); Associated with Charcot-Marie-Tooth disease type 2A2.

How common is MFN2 p.Val136= (c.408A>T) in the general population?

MFN2 p.Val136= (c.408A>T) is low-frequency (popmax 3.64%, eas) (gnomAD).

MFN2 p.Val136=

Q: What condition is associated with MFN2 p.Val136= (c.408A>T)?

MFN2 p.Val136= (c.408A>T) 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).

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.408A>T · rs78814413 · VCV138210

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.64%, eas)

Conditions

Charcot-Marie-Tooth disease type 2A2

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 -0.93	GERP -5.4
Overall
CADD	2.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.64% East Asian · 1,635/44,880 alleles

Filtering AF 3.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.44%

Overall 0.189% 3,056/1,614,220 alleles · low-frequency exomes 2,775/1,461,880 · genomes 281/152,340 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	3.64%	27
South Asian	1.3%	77
Remaining individualsnot grpmax-eligible	0.294%	340
Middle Eastern	0.0825%	1,212
Admixed American	0.0117%	8,575
African / African-American	0.00799%	12,511
European (non-Finnish)	0.00263%	38,066

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.Val136=
Coding: c.408A>T
MANE Select: NM_014874
dbSNP: rs78814413
Type: single nucleotide variant
Location: chr1:11996252 (GRCh38)
Gene constraint: LOEUF 0.602 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 3 PDB
Residue 136: a β-strand; the dynamin-type g domain

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 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.Val136Leu Uncertain significance ★ ⚠ same residue
MFN2 p.Val136fs Pathogenic/Likely pathogenic ★★ 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-val136 (accessed [today's date]).

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