Is MORC2 p.Ala448Val (c.1343C>T) pathogenic?

MORC2 p.Ala448Val (c.1343C>T) is classified Uncertain significance in MORC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-15). AlphaMissense: likely benign (0.0848); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with MORC2 p.Ala448Val (c.1343C>T)?

MORC2 p.Ala448Val (c.1343C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MORC2 p.Ala448Val (c.1343C>T) in the general population?

MORC2 p.Ala448Val (c.1343C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MORC2 p.Ala448Val (c.1343C>T)?

AlphaMissense predicts likely benign (score 0.0848) — an in-silico prediction, not a clinical call.

MORC2 p.Ala448Val

c.1343C>T · rs958295807 · VCV1770411

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0848	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -7.05	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 9.7	GERP 0.64, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 2,611 bp · p 4.1e-09 · regional, not allelic
Overall
CADD	23.0	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 0.00267% African / African-American · 2/75,000 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,614,100 alleles · very rare exomes 4/1,461,886 · genomes 0/152,214 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,500
South Asian	0.0011%	91,084
European (non-Finnish)	8.47e-05%	1,180,032

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.Ala448Val
Coding: c.1343C>T
MANE Select: NM_001303256
dbSNP: rs958295807
Type: single nucleotide variant
Location: chr22:30937841 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.37 · 9 PDB
Residue 448: 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

Similar variants

MORC2 p.Ala448= Likely benign ★★ same residue
MORC2 p.Tyr394Cys Pathogenic/Likely pathogenic ★★ same condition
MORC2 c.68+4A>C Uncertain significance ★★ same condition
MORC2 p.Ala741Thr Uncertain significance ★★ ⚠ same condition
MORC2 p.Arg287Cys Uncertain significance ★★ ⚠ same condition
MORC2 p.Arg535Trp Uncertain significance ★★ ⚠ same condition
MORC2 p.Arg608His Uncertain significance ★★ ⚠ same condition
MORC2 p.Arg642Gln Uncertain significance ★★ ⚠ 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-ala448val (accessed [today's date]).

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