Is AXIN2 p.Pro498= (c.1494C>T) pathogenic?

AXIN2 p.Pro498= (c.1494C>T) is classified Conflicting classifications of pathogenicity in AXIN2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.0167%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with AXIN2 p.Pro498= (c.1494C>T)?

AXIN2 p.Pro498= (c.1494C>T) is associated with hereditary neoplastic syndrome, oligodontia-cancer predisposition syndrome (ClinVar).

How common is AXIN2 p.Pro498= (c.1494C>T) in the general population?

AXIN2 p.Pro498= (c.1494C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

AXIN2 p.Pro498=

c.1494C>T · rs1353761854 · VCV762340

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Conditions

hereditary neoplastic 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 -3.6	GERP -3.1
Overall
CADD	3.921	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/6,002 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.00062% 10/1,613,040 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	6,002
East Asian	0.00447%	22,371
European (non-Finnish)	0.000593%	168,539

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.Pro498=
Coding: c.1494C>T
MANE Select: NM_004655
dbSNP: rs1353761854
Type: single nucleotide variant
Location: chr17:65537542 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.71 · 1 PDB

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.Pro498Ala Uncertain significance ★★ ⚠ same residue
AXIN2 p.Pro498His Uncertain significance ★★ ⚠ same residue
AXIN2 p.Pro498Leu Uncertain significance ★★ ⚠ same residue
AXIN2 p.Pro498Ser Uncertain significance ★★ ⚠ same residue
AXIN2 p.Pro498Arg 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-pro498 (accessed [today's date]).

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