Is MORC2 p.Arg287Cys (c.859C>T) pathogenic?

MORC2 p.Arg287Cys (c.859C>T) is classified Uncertain significance in MORC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-07). AlphaMissense: likely pathogenic (0.988); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with MORC2 p.Arg287Cys (c.859C>T)?

MORC2 p.Arg287Cys (c.859C>T) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease axonal type 2Z (ClinVar).

How common is MORC2 p.Arg287Cys (c.859C>T) in the general population?

MORC2 p.Arg287Cys (c.859C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MORC2 p.Arg287Cys (c.859C>T)?

AlphaMissense predicts likely pathogenic (score 0.988) — an in-silico prediction, not a clinical call.

MORC2 p.Arg287Cys

c.859C>T · rs2040732647 · VCV1763978

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.988	likely pathogenic · top 10% in MORC2
REVEL	0.214	benign-leaning
SaProt	LLR -14.41	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 8,285 bp · p 7.2e-07 · regional, not allelic
Overall
CADD	31.0	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 0.00133% African / African-American · 1/74,994 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,048 alleles · very rare exomes 6/1,461,880 · genomes 0/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,994
European (non-Finnish)	0.000424%	236,003

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.Arg287Cys
Coding: c.859C>T
MANE Select: NM_001303256
dbSNP: rs2040732647
Type: single nucleotide variant
Location: chr22:30940803 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.37 · 9 PDB
Residue 287: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease axonal type 2Z

Similar variants

MORC2 p.Arg287Leu 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-arg287cys (accessed [today's date]).

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