Is MFN2 p.Ser378Pro (c.1132T>C) pathogenic?

MFN2 p.Ser378Pro (c.1132T>C) is classified Conflicting classifications of pathogenicity in MFN2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-23). AlphaMissense: likely pathogenic (0.8468); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 2A2.

What condition is associated with MFN2 p.Ser378Pro (c.1132T>C)?

MFN2 p.Ser378Pro (c.1132T>C) is associated with Charcot-Marie-Tooth disease type 2A2, Charcot-Marie-Tooth disease (ClinVar).

How common is MFN2 p.Ser378Pro (c.1132T>C) in the general population?

MFN2 p.Ser378Pro (c.1132T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MFN2 p.Ser378Pro (c.1132T>C)?

AlphaMissense predicts likely pathogenic (score 0.8468) — an in-silico prediction, not a clinical call.

MFN2 p.Ser378Pro

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.1132T>C · rs1569854381 · VCV637717

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8468 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2A2

Computational evidence

Protein change
AlphaMissense	0.8468	likely pathogenic
REVEL	0.79	moderately pathogenic-leaning
SaProt	LLR -7.65	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 13 kb · p 0.00012 · regional, not allelic
Overall
CADD	23.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MFN2
Protein: p.Ser378Pro
Coding: c.1132T>C
MANE Select: NM_014874
dbSNP: rs1569854381
Type: single nucleotide variant
Location: chr1:12002075 (GRCh38)
Gene constraint: LOEUF 0.602 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 3 PDB
Residue 378: an α-helix; the 'part of a helix bundle domain, formed by helices from n-terminal and c-terminal regions' region

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: Charcot-Marie-Tooth disease

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

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

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.Ala738Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
MFN2 p.Arg104Gln Likely pathogenic ★★ same condition
MFN2 p.Arg104Trp Pathogenic ★★ same condition
MFN2 p.Arg259Cys Pathogenic/Likely pathogenic ★★ same condition
MFN2 p.Arg259Leu 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-ser378pro (accessed [today's date]).

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