Is AXIN2 p.Val280Ala (c.839T>C) pathogenic?

AXIN2 p.Val280Ala (c.839T>C) is classified Conflicting classifications of pathogenicity in AXIN2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-09). AlphaMissense: likely benign (0.0986); Very rare (popmax 0.00133%, afr); Associated with oligodontia-cancer predisposition syndrome.

What condition is associated with AXIN2 p.Val280Ala (c.839T>C)?

AXIN2 p.Val280Ala (c.839T>C) is associated with oligodontia-cancer predisposition syndrome, hereditary neoplastic syndrome (ClinVar).

How common is AXIN2 p.Val280Ala (c.839T>C) in the general population?

AXIN2 p.Val280Ala (c.839T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about AXIN2 p.Val280Ala (c.839T>C)?

AlphaMissense predicts likely benign (score 0.0986) — an in-silico prediction, not a clinical call.

AXIN2 p.Val280Ala

c.839T>C · rs1489180181 · VCV947228

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

oligodontia-cancer predisposition syndrome

Computational evidence

Protein change
AlphaMissense	0.0986	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -6.48	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 4.7	GERP 1, phastCons 0.22
Regional constraint	o/e 1.08	unconstrained · MANE · 25 kb · p 0.011 · regional, not allelic
Overall
CADD	14.53	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 0.00133% African / African-American · 1/74,924 alleles

Overall 0.000138% 2/1,450,712 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,924
South Asian	0.00113%	88,846

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.Val280Ala
Coding: c.839T>C
MANE Select: NM_004655
dbSNP: rs1489180181
Type: single nucleotide variant
Location: chr17:65549637 (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

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

Also linked: hereditary neoplastic syndrome

Similar variants

AXIN2 p.Val280Ile Uncertain significance ★ same residue
AXIN2 p.Val280Phe 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
AXIN2 c.816-1G>A 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-val280ala (accessed [today's date]).

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