Is CTNNB1 p.Asp727Glu (c.2181T>G) pathogenic?

CTNNB1 p.Asp727Glu (c.2181T>G) is classified Uncertain significance in CTNNB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-02). AlphaMissense: likely benign (0.0949); Very rare (popmax 0.000254%, nfe); Associated with exudative vitreoretinopathy 7.

What condition is associated with CTNNB1 p.Asp727Glu (c.2181T>G)?

CTNNB1 p.Asp727Glu (c.2181T>G) is associated with exudative vitreoretinopathy 7 (ClinVar).

How common is CTNNB1 p.Asp727Glu (c.2181T>G) in the general population?

CTNNB1 p.Asp727Glu (c.2181T>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Familial exudative vitreoretinopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CTNNB1 p.Asp727Glu (c.2181T>G)?

AlphaMissense predicts likely benign (score 0.0949) — an in-silico prediction, not a clinical call.

CTNNB1 p.Asp727Glu

c.2181T>G · rs2125653234 · VCV1806007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

exudative vitreoretinopathy 7

Computational evidence

Protein change
AlphaMissense	0.0949	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -6.84	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 -3.2	GERP -1.5
Regional constraint	o/e 0.78	unconstrained · MANE · 2,665 bp · p 0.012 · regional, not allelic
Overall
CADD	15.89	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 0.000254% European (non-Finnish) · 3/1,180,030 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,870 alleles · very rare

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: CTNNB1
Protein: p.Asp727Glu
Coding: c.2181T>G
MANE Select: NM_001904
dbSNP: rs2125653234
Type: single nucleotide variant
Location: chr3:41239177 (GRCh38)
Gene constraint: LOEUF 0.139 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.02 · 50 PDB
Residue 727: the 'disordered' region; a UniProt-annotated variant site (in nedsdv; the patient also manifest features of exudative vitreoretinopathy)

Full CTNNB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

exudative vitreoretinopathy 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial exudative vitreoretinopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

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CTNNB1 p.Thr41Ala Likely pathogenic ★★ ⚠ same condition
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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/ctnnb1-p-asp727glu (accessed [today's date]).

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