Is MFN2 p.Arg397Pro (c.1190G>C) pathogenic?

MFN2 p.Arg397Pro (c.1190G>C) is classified Uncertain significance in MFN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-05). AlphaMissense: likely pathogenic (0.9332); Absent from gnomAD v4.1.

How common is MFN2 p.Arg397Pro (c.1190G>C) in the general population?

MFN2 p.Arg397Pro (c.1190G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MFN2 p.Arg397Pro (c.1190G>C)?

AlphaMissense predicts likely pathogenic (score 0.9332) — an in-silico prediction, not a clinical call.

MFN2 p.Arg397Pro

c.1190G>C · rs778219078 · VCV1308425

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9332 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9332	likely pathogenic
REVEL	0.628	indeterminate
SaProt	LLR -9.04	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 13 kb · p 0.00012 · regional, not allelic
Overall
CADD	23.8	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.Arg397Pro
Coding: c.1190G>C
MANE Select: NM_014874
dbSNP: rs778219078
Type: single nucleotide variant
Location: chr1:12004021 (GRCh38)
Gene constraint: LOEUF 0.602 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.94 · 3 PDB
Residue 397: an α-helix

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

Similar variants

MFN2 p.Arg397Gln Uncertain significance ★★ ⚠ same residue
MFN2 p.Arg397Trp Uncertain significance ★★ ⚠ same residue
MFN2 p.Arg397= Likely benign ★ same residue
MFN2 p.Arg397_Gln398insLysArg Uncertain significance ★ same residue
MFN2 c.1160+1G>A Likely pathogenic ★★ same type
MFN2 c.475-1G>C Pathogenic ★★ same type
MFN2 p.Ala166Val Pathogenic/Likely pathogenic ★★ ⚠ same type
MFN2 p.Ala220Thr Pathogenic/Likely pathogenic ★★ same type

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-arg397pro (accessed [today's date]).

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