Is MORC2 p.Glu751del (c.2247GGA[1]) pathogenic?

MORC2 p.Glu751del (c.2247GGA[1]) is classified Uncertain significance in MORC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-08). Very rare (popmax 0.00134%, afr); Associated with Charcot-Marie-Tooth disease axonal type 2Z.

What condition is associated with MORC2 p.Glu751del (c.2247GGA[1])?

MORC2 p.Glu751del (c.2247GGA[1]) is associated with Charcot-Marie-Tooth disease axonal type 2Z (ClinVar).

How common is MORC2 p.Glu751del (c.2247GGA[1]) in the general population?

MORC2 p.Glu751del (c.2247GGA[1]) is very rare (popmax 0.00134%, afr) (gnomAD).

MORC2 p.Glu751del

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.2247GGA[1] · rs1247915167 · VCV566523

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

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 -0.78	GERP -3.9
Overall
CADD	18.17	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(CCT)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,904 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,614,024 alleles · very rare exomes 5/1,461,882 · genomes 2/152,142 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,904
European (non-Finnish)	0.000508%	196,673

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.Glu751del
Coding: c.2247GGA[1]
MANE Select: NM_001303256
dbSNP: rs1247915167
Type: Microsatellite
Location: chr22:30934133 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.37 · 9 PDB
Residue 751: 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 c.123-14_123-10del Likely benign ★★ same condition
MORC2 p.409GVV[3] Uncertain significance ★ same condition
MORC2 p.Gln694del Uncertain significance ★ same condition
MORC2 c.1215-14_1215-13del Likely benign ★ same condition
MORC2 c.1738-15_1738-13del Likely benign ★ same condition
MORC2 c.1738-19_1738-17del Likely benign ★ same condition
MORC2 c.2748-6_2748-4del Likely benign ★ same condition
MORC2 p.Arg132Cys 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/morc2-p-glu751del (accessed [today's date]).

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