Is MORC2 p.Val709Ile (c.2125G>A) pathogenic?

MORC2 p.Val709Ile (c.2125G>A) is classified Uncertain significance in MORC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-19). AlphaMissense: likely benign (0.0676); Very rare (popmax 0.00935%, afr); Associated with Inborn genetic diseases.

What condition is associated with MORC2 p.Val709Ile (c.2125G>A)?

MORC2 p.Val709Ile (c.2125G>A) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease axonal type 2Z (ClinVar).

How common is MORC2 p.Val709Ile (c.2125G>A) in the general population?

MORC2 p.Val709Ile (c.2125G>A) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about MORC2 p.Val709Ile (c.2125G>A)?

AlphaMissense predicts likely benign (score 0.0676) — an in-silico prediction, not a clinical call.

MORC2 p.Val709Ile

c.2125G>A · rs1015638849 · VCV1786313

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0676 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0676	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.43	GERP -3.6
Regional constraint	o/e 1.02	unconstrained · MANE · 1,093 bp · p 0.79 · regional, not allelic
Overall
CADD	4.722	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00935% African / African-American · 7/74,882 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00173% 28/1,614,006 alleles · very rare exomes 24/1,461,888 · genomes 4/152,118 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,697
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.00161%	62,106

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.Val709Ile
Coding: c.2125G>A
MANE Select: NM_001303256
dbSNP: rs1015638849
Type: single nucleotide variant
Location: chr22:30934849 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.37 · 9 PDB
Residue 709: the 'disordered' region

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.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-val709ile (accessed [today's date]).

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