Is AXIN2 p.Pro483Arg (c.1448C>G) pathogenic?

AXIN2 p.Pro483Arg (c.1448C>G) is classified Conflicting classifications of pathogenicity in AXIN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.0792); Very rare (popmax 0.00509%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with AXIN2 p.Pro483Arg (c.1448C>G)?

AXIN2 p.Pro483Arg (c.1448C>G) is associated with hereditary neoplastic syndrome, oligodontia-cancer predisposition syndrome (ClinVar).

How common is AXIN2 p.Pro483Arg (c.1448C>G) in the general population?

AXIN2 p.Pro483Arg (c.1448C>G) is very rare (popmax 0.00509%, amr) (gnomAD).

What do computational predictors say about AXIN2 p.Pro483Arg (c.1448C>G)?

AlphaMissense predicts likely benign (score 0.0792) — an in-silico prediction, not a clinical call.

AXIN2 p.Pro483Arg

c.1448C>G · rs530465133 · VCV639760

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00509%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0792	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -7.64	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 1.5	GERP -2.7, phastCons 0.002
Regional constraint	o/e 1.08	unconstrained · MANE · 25 kb · p 0.011 · regional, not allelic
Overall
CADD	18.37	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

Grpmax group 0.00509% Admixed American · 3/58,944 alleles

Filtering AF 0.00135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000674%

Overall 0.000436% 7/1,606,490 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00509%	19,648
African / African-American	0.004%	24,993
Remaining individualsnot grpmax-eligible	0.00161%	62,292

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.Pro483Arg
Coding: c.1448C>G
MANE Select: NM_004655
dbSNP: rs530465133
Type: single nucleotide variant
Location: chr17:65537588 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.71 · 1 PDB
Residue 483: the 'disordered' region

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

Also linked: oligodontia-cancer predisposition syndrome

Similar variants

AXIN2 p.Pro483Ala Uncertain significance ★★ ⚠ same residue
AXIN2 p.Pro483Leu Uncertain significance ★★ ⚠ same residue
AXIN2 p.Pro483Ser Uncertain significance ★★ ⚠ same residue
AXIN2 p.Pro483= Benign/Likely benign ★★ same residue
AXIN2 p.Pro483His 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

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-pro483arg (accessed [today's date]).

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