Is AXIN2 p.Arg399= (c.1195C>A) pathogenic?

AXIN2 p.Arg399= (c.1195C>A) is classified Benign/Likely benign in AXIN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-10). Very rare (popmax 0.000339%, nfe); Associated with oligodontia-cancer predisposition syndrome.

What condition is associated with AXIN2 p.Arg399= (c.1195C>A)?

AXIN2 p.Arg399= (c.1195C>A) is associated with oligodontia-cancer predisposition syndrome, hereditary neoplastic syndrome (ClinVar).

How common is AXIN2 p.Arg399= (c.1195C>A) in the general population?

AXIN2 p.Arg399= (c.1195C>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

AXIN2 p.Arg399=

c.1195C>A · rs1157452251 · VCV1149800

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

oligodontia-cancer predisposition syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP -0.38, phastCons 1
Overall
CADD	10.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,050 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,864 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: AXIN2
Protein: p.Arg399=
Coding: c.1195C>A
MANE Select: NM_004655
dbSNP: rs1157452251
Type: single nucleotide variant
Location: chr17:65538208 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.71 · 1 PDB
Residue 399: the 'interaction with gsk3b' region; the 'disordered' region

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

Disease context

oligodontia-cancer predisposition syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

Similar variants

AXIN2 p.Arg399Gln Uncertain significance ★★ ⚠ same residue
AXIN2 p.Arg399Gly Uncertain significance ★★ ⚠ same residue
AXIN2 p.Arg399Pro Uncertain significance ★ ⚠ same residue
AXIN2 p.Arg399Ter Conflicting classifications of pathogenicity ★ ⚠ same residue
AXIN2 p.Arg399fs Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg399 (accessed [today's date]).

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