Is MFN2 p.Pro201Ser (c.601C>T) pathogenic?

MFN2 p.Pro201Ser (c.601C>T) is classified Uncertain significance in MFN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-05). AlphaMissense: likely pathogenic (0.9951); Absent from gnomAD v4.1; Associated with neuropathy, hereditary motor and sensory, type 6A.

How common is MFN2 p.Pro201Ser (c.601C>T) in the general population?

MFN2 p.Pro201Ser (c.601C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MFN2 p.Pro201Ser (c.601C>T)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

MFN2 p.Pro201Ser

Q: What condition is associated with MFN2 p.Pro201Ser (c.601C>T)?

MFN2 p.Pro201Ser (c.601C>T) is associated with neuropathy, hereditary motor and sensory, type 6A, Charcot-Marie-Tooth disease type 2 (ClinVar).

c.601C>T · rs1639041254 · VCV962976

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuropathy, hereditary motor and sensory, type 6A

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic · top 6% in MFN2
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -15.04	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 9,784 bp · p 1.5e-16 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Pro201Ser
Coding: c.601C>T
MANE Select: NM_014874
dbSNP: rs1639041254
Type: single nucleotide variant
Location: chr1:11998771 (GRCh38)
Gene constraint: LOEUF 0.602 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 3 PDB
Residue 201: the 'g3 motif' region; an α-helix; the dynamin-type g domain

Full MFN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuropathy, hereditary motor and sensory, type 6A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 2

Similar variants

MFN2 p.Pro201= Likely benign ★ 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-pro201ser (accessed [today's date]).

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