Is MFN2 p.Pro587Ser (c.1759C>T) pathogenic?

MFN2 p.Pro587Ser (c.1759C>T) is classified Uncertain significance in MFN2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-16). AlphaMissense: likely benign (0.1695); Ultra-rare (popmax 0.0329%, mid); Associated with Charcot-Marie-Tooth disease type 2A2.

What condition is associated with MFN2 p.Pro587Ser (c.1759C>T)?

MFN2 p.Pro587Ser (c.1759C>T) is associated with Charcot-Marie-Tooth disease type 2A2, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2 (ClinVar).

How common is MFN2 p.Pro587Ser (c.1759C>T) in the general population?

MFN2 p.Pro587Ser (c.1759C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about MFN2 p.Pro587Ser (c.1759C>T)?

AlphaMissense predicts likely benign (score 0.1695) — an in-silico prediction, not a clinical call.

MFN2 p.Pro587Ser

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.1759C>T · rs771675874 · VCV694952

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1695 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 2A2

Computational evidence

Protein change
AlphaMissense	0.1695	likely benign
REVEL	0.496	indeterminate
SaProt	LLR -6.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 13 kb · p 0.00012 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.00605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00565%

Overall 0.00558% 90/1,614,130 alleles · ultra-rare exomes 82/1,461,884 · genomes 8/152,246 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
European (non-Finnish)	0.00737%	13,564
South Asian	0.0011%	91,096

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.Pro587Ser
Coding: c.1759C>T
MANE Select: NM_014874
dbSNP: rs771675874
Type: single nucleotide variant
Location: chr1:12006580 (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 2A2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease Charcot-Marie-Tooth disease type 2 Charcot-Marie-Tooth disease type 4

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

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

MFN2 p.Pro587Thr Uncertain significance ★★ ⚠ same residue
MFN2 p.Pro587Ala 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

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-pro587ser (accessed [today's date]).

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