Is MORC2 p.Val397= (c.1191G>A) pathogenic?

MORC2 p.Val397= (c.1191G>A) is classified Likely benign in MORC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-14). Ultra-rare (popmax 0.0178%, eas); Associated with Charcot-Marie-Tooth disease axonal type 2Z.

What condition is associated with MORC2 p.Val397= (c.1191G>A)?

MORC2 p.Val397= (c.1191G>A) is associated with Charcot-Marie-Tooth disease axonal type 2Z (ClinVar).

How common is MORC2 p.Val397= (c.1191G>A) in the general population?

MORC2 p.Val397= (c.1191G>A) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

MORC2 p.Val397=

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.1191G>A · rs777200130 · VCV2954926

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Conditions

Charcot-Marie-Tooth disease axonal type 2Z

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.22	donor gain · deltas
Constraint at this position
Conservation	phyloP 0.38	GERP -0.38, phastCons 0.99
Overall
CADD	13.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,892 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000496% 8/1,614,040 alleles · ultra-rare exomes 7/1,461,892 · genomes 1/152,148 · 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.Val397=
Coding: c.1191G>A
MANE Select: NM_001303256
dbSNP: rs777200130
Type: single nucleotide variant
Location: chr22:30938088 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.37 · 9 PDB

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.Arg132Cys Pathogenic/Likely pathogenic ★★ same condition
MORC2 p.Arg252Trp Pathogenic/Likely pathogenic ★★ same condition
MORC2 p.Arg266Ser Pathogenic/Likely pathogenic ★★ same condition
MORC2 p.Asp466Asn Pathogenic/Likely pathogenic ★★ ⚠ same condition
MORC2 p.Glu236Gly Pathogenic/Likely pathogenic ★★ same condition
MORC2 p.Glu27Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
MORC2 p.Ser87Leu Pathogenic ★★ same condition
MORC2 p.Thr24Ile 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-val397 (accessed [today's date]).

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