Is MORC2 p.Ala975Asp (c.2924C>A) pathogenic?

MORC2 p.Ala975Asp (c.2924C>A) is classified Uncertain significance in MORC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-12). AlphaMissense: likely benign (0.2851); Very rare (popmax 0.00133%, afr).

How common is MORC2 p.Ala975Asp (c.2924C>A) in the general population?

MORC2 p.Ala975Asp (c.2924C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MORC2 p.Ala975Asp (c.2924C>A)?

AlphaMissense predicts likely benign (score 0.2851) — an in-silico prediction, not a clinical call.

MORC2 p.Ala975Asp

c.2924C>A · rs1569186001 · VCV2505060

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2851	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -7.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP -0.41, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 7,374 bp · p 2e-10 · regional, not allelic
Overall
CADD	23.4	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 0.00133% African / African-American · 1/75,036 alleles

Overall 6.2e-05% 1/1,614,136 alleles · very rare exomes 1/1,461,876 · genomes 0/152,260 · 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.Ala975Asp
Coding: c.2924C>A
MANE Select: NM_001303256
dbSNP: rs1569186001
Type: single nucleotide variant
Location: chr22:30928125 (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

Similar variants

MORC2 p.Ala975Val Uncertain significance ★ ⚠ same residue
MORC2 p.Arg132Cys Pathogenic/Likely pathogenic ★★ same type
MORC2 p.Arg132His Pathogenic/Likely pathogenic ★★ ⚠ same type
MORC2 p.Arg252Trp Pathogenic/Likely pathogenic ★★ same type
MORC2 p.Arg266Ser Pathogenic/Likely pathogenic ★★ same type
MORC2 p.Asp466Asn Pathogenic/Likely pathogenic ★★ ⚠ same type
MORC2 p.Glu236Gly Pathogenic/Likely pathogenic ★★ same type
MORC2 p.Glu27Lys Pathogenic/Likely pathogenic ★★ ⚠ same type

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-ala975asp (accessed [today's date]).

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