Is AXIN2 p.Pro776Ala (c.2326C>G) pathogenic?

AXIN2 p.Pro776Ala (c.2326C>G) is classified Uncertain significance in AXIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). AlphaMissense: likely pathogenic (0.9664); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with AXIN2 p.Pro776Ala (c.2326C>G)?

AXIN2 p.Pro776Ala (c.2326C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is AXIN2 p.Pro776Ala (c.2326C>G) in the general population?

AXIN2 p.Pro776Ala (c.2326C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AXIN2 p.Pro776Ala (c.2326C>G)?

AlphaMissense predicts likely pathogenic (score 0.9664) — an in-silico prediction, not a clinical call.

AXIN2 p.Pro776Ala

c.2326C>G · VCV3814365

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9664 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9664	likely pathogenic · top 7% in AXIN2
REVEL	0.765	pathogenic-leaning
SaProt	LLR -8.06	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 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 4,033 bp · p 0.0017 · regional, not allelic
Overall
CADD	29.5	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: AXIN2
Protein: p.Pro776Ala
Coding: c.2326C>G
MANE Select: NM_004655
Type: single nucleotide variant
Location: chr17:65533991 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.71 · 1 PDB
Residue 776: the dix domain

Full AXIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AXIN2 p.Pro776= Benign/Likely benign ★★ same residue
AXIN2 p.Pro776fs Pathogenic ★ same residue
AXIN2 p.Pro776Ser Uncertain significance ★ ⚠ same residue
AXIN2 c.1060-1G>C Likely pathogenic ★★ same condition
AXIN2 c.1200+1G>A Likely pathogenic ★★ same condition
AXIN2 c.1201-1G>C Likely pathogenic ★★ same condition
AXIN2 c.1713-1G>A Likely pathogenic ★★ same condition
AXIN2 c.815+1G>A Pathogenic/Likely 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/axin2-p-pro776ala (accessed [today's date]).

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