Is CTNNB1 p.Phe683Ser (c.2048T>C) pathogenic?

CTNNB1 p.Phe683Ser (c.2048T>C) is classified Uncertain significance in CTNNB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-10). AlphaMissense: likely pathogenic (0.9841); Absent from gnomAD v4.1.

How common is CTNNB1 p.Phe683Ser (c.2048T>C) in the general population?

CTNNB1 p.Phe683Ser (c.2048T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTNNB1 p.Phe683Ser (c.2048T>C)?

AlphaMissense predicts likely pathogenic (score 0.9841) — an in-silico prediction, not a clinical call.

CTNNB1 p.Phe683Ser

c.2048T>C · rs2125647365 · VCV2446654

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9841 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9841	likely pathogenic
REVEL	0.644	pathogenic-leaning
SaProt	LLR -4.79	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 2,665 bp · p 0.012 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

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.Phe683Ser
Coding: c.2048T>C
MANE Select: NM_001904
dbSNP: rs2125647365
Type: single nucleotide variant
Location: chr3:41236681 (GRCh38)
Gene constraint: LOEUF 0.139 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.02 · 50 PDB
Residue 683: 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

Similar variants

CTNNB1 c.1081+1G>T Pathogenic/Likely pathogenic ★★ same type
CTNNB1 c.1082-1G>C Pathogenic ★★ same type
CTNNB1 c.735-1G>C Pathogenic ★★ same type
CTNNB1 p.Arg474Ter Pathogenic ★★ same type
CTNNB1 p.Arg515Ter Pathogenic ★★ same type
CTNNB1 p.Arg535Ter Pathogenic ★★ same type
CTNNB1 p.Arg587Ter Pathogenic/Likely pathogenic ★★ same type
CTNNB1 p.Arg661Ter 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/ctnnb1-p-phe683ser (accessed [today's date]).

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