Is MORC2 p.Arg307Trp (c.919C>T) pathogenic?

MORC2 p.Arg307Trp (c.919C>T) is classified Uncertain significance in MORC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). AlphaMissense: likely benign (0.2393); Very rare (popmax 0.005%, amr); Associated with Charcot-Marie-Tooth disease axonal type 2Z.

What condition is associated with MORC2 p.Arg307Trp (c.919C>T)?

MORC2 p.Arg307Trp (c.919C>T) is associated with Charcot-Marie-Tooth disease axonal type 2Z (ClinVar).

How common is MORC2 p.Arg307Trp (c.919C>T) in the general population?

MORC2 p.Arg307Trp (c.919C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about MORC2 p.Arg307Trp (c.919C>T)?

AlphaMissense predicts likely benign (score 0.2393) — an in-silico prediction, not a clinical call.

MORC2 p.Arg307Trp

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.919C>T · rs772692197 · VCV1046847

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2393 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease axonal type 2Z

Computational evidence

Protein change
AlphaMissense	0.2393	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -11.05	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.1	GERP -0.18, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 8,285 bp · p 7.2e-07 · regional, not allelic
Overall
CADD	26.0	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

Grpmax group 0.005% Admixed American · 3/59,994 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00248% 40/1,613,520 alleles · very rare exomes 36/1,461,364 · genomes 4/152,156 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,998
African / African-American	0.00401%	24,969
South Asian	0.00329%	30,355
European (non-Finnish)	0.00254%	39,334
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Arg307Trp
Coding: c.919C>T
MANE Select: NM_001303256
dbSNP: rs772692197
Type: single nucleotide variant
Location: chr22:30940027 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.37 · 9 PDB
Residue 307: an α-helix

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.Arg307Gln Uncertain significance ★ ⚠ same residue
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

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-arg307trp (accessed [today's date]).

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