Is MORC2 p.Pro645del (c.1933_1935del) pathogenic?

MORC2 p.Pro645del (c.19331935del) is classified Uncertain significance in MORC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-29). Very rare (popmax 0.00169%, nfe); Associated with Charcot-Marie-Tooth disease axonal type 2Z.

What condition is associated with MORC2 p.Pro645del (c.1933_1935del)?

MORC2 p.Pro645del (c.1933_1935del) is associated with Charcot-Marie-Tooth disease axonal type 2Z (ClinVar).

How common is MORC2 p.Pro645del (c.1933_1935del) in the general population?

MORC2 p.Pro645del (c.1933_1935del) is very rare (popmax 0.00169%, nfe) (gnomAD).

MORC2 p.Pro645del

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2Z inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1933_1935del · VCV3617184

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Conditions

Charcot-Marie-Tooth disease axonal type 2Z

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.069	GERP -1.8, phastCons 0.04

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% European (non-Finnish) · 20/1,180,026 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00124% 20/1,614,040 alleles · very rare exomes 20/1,461,874 · genomes 0/152,166 · joint denominator

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: MORC2
Protein: p.Pro645del
Coding: c.1933_1935del
MANE Select: NM_001303256
Type: Deletion
Location: chr22:30935039 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.37 · 9 PDB
Residue 645: the 'disordered' region

Full MORC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease axonal type 2Z — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal

Similar variants

MORC2 p.Pro645= Likely benign ★ same residue
MORC2 c.158-12del Benign/Likely benign ★★ same condition
MORC2 c.2747+5_2747+6del Benign/Likely benign ★★ same condition
MORC2 c.2747+4del Uncertain significance ★ same condition
MORC2 c.988-27_988-18del Uncertain significance ★ same condition
MORC2 c.988-2del Uncertain significance ★ same condition
MORC2 p.Glu992_Lys993del Uncertain significance ★ same condition
MORC2 p.Lys361fs Uncertain significance ★ 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/morc2-p-pro645del (accessed [today's date]).

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