Is AXIN2 p.Ala728= (c.2184C>T) pathogenic?

AXIN2 p.Ala728= (c.2184C>T) is classified Benign/Likely benign in AXIN2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-21). Ultra-rare (popmax 0.0107%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with AXIN2 p.Ala728= (c.2184C>T)?

AXIN2 p.Ala728= (c.2184C>T) is associated with hereditary neoplastic syndrome, oligodontia-cancer predisposition syndrome (ClinVar).

How common is AXIN2 p.Ala728= (c.2184C>T) in the general population?

AXIN2 p.Ala728= (c.2184C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

AXIN2 p.Ala728=

c.2184C>T · rs146547133 · VCV240008

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

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 2.4	GERP -0.38, phastCons 0.99
Overall
CADD	3.212	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,914 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00155% 25/1,614,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,364
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.00127%	78,670
South Asian	0.0011%	91,084

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.Ala728=
Coding: c.2184C>T
MANE Select: NM_004655
dbSNP: rs146547133
Type: single nucleotide variant
Location: chr17:65535679 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.71 · 1 PDB
Residue 728: 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.Ala728Gly Uncertain significance ★★ ⚠ same residue
AXIN2 p.Ala728Ser Uncertain significance ★★ ⚠ same residue
AXIN2 p.Ala728Thr 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
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-ala728 (accessed [today's date]).

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