Is CTNNB1 p.Arg661Pro (c.1982G>C) pathogenic?

CTNNB1 p.Arg661Pro (c.1982G>C) is classified Uncertain significance in CTNNB1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-12). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with severe intellectual disability-progressive spastic diplegia syndrome.

What condition is associated with CTNNB1 p.Arg661Pro (c.1982G>C)?

CTNNB1 p.Arg661Pro (c.1982G>C) is associated with severe intellectual disability-progressive spastic diplegia syndrome (ClinVar).

How common is CTNNB1 p.Arg661Pro (c.1982G>C) in the general population?

CTNNB1 p.Arg661Pro (c.1982G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTNNB1 p.Arg661Pro (c.1982G>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

CTNNB1 p.Arg661Pro

c.1982G>C · rs2125647004 · VCV1333222

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

severe intellectual disability-progressive spastic diplegia syndrome

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 6% in CTNNB1
REVEL	0.57	indeterminate
SaProt	LLR -15.01	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.12	constrained · MANE · 60 bp · p 1.3e-05 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTNNB1
Protein: p.Arg661Pro
Coding: c.1982G>C
MANE Select: NM_001904
dbSNP: rs2125647004
Type: single nucleotide variant
Location: chr3:41236615 (GRCh38)
Gene constraint: LOEUF 0.139 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.02 · 50 PDB
Residue 661: an α-helix; 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

severe intellectual disability-progressive spastic diplegia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CTNNB1 p.Arg661Ter Pathogenic/Likely pathogenic ★★ same residue
CTNNB1 p.Arg661fs Pathogenic ★★ same residue
CTNNB1 p.Arg661= Benign/Likely benign ★★ same residue
CTNNB1 p.Arg661Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CTNNB1 c.1082-1G>C Pathogenic ★★ same condition
CTNNB1 p.Arg474Ter Pathogenic ★★ same condition
CTNNB1 p.Arg515Ter Pathogenic ★★ same condition
CTNNB1 p.Arg535Ter 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/ctnnb1-p-arg661pro (accessed [today's date]).

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