Is AXIN2 p.Ala4Thr (c.10G>A) pathogenic?

AXIN2 p.Ala4Thr (c.10G>A) is classified Uncertain significance in AXIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-14). AlphaMissense: likely benign (0.0753); Very rare (popmax 0.0011%, sas); Associated with oligodontia-cancer predisposition syndrome.

What condition is associated with AXIN2 p.Ala4Thr (c.10G>A)?

AXIN2 p.Ala4Thr (c.10G>A) is associated with oligodontia-cancer predisposition syndrome (ClinVar).

How common is AXIN2 p.Ala4Thr (c.10G>A) in the general population?

AXIN2 p.Ala4Thr (c.10G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about AXIN2 p.Ala4Thr (c.10G>A)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

AXIN2 p.Ala4Thr

c.10G>A · rs1175877868 · VCV1443116

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

oligodontia-cancer predisposition syndrome

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -6.42	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 2.6	GERP 0.42, phastCons 0.99
Regional constraint	o/e 1.11	unconstrained · MANE · 45 bp · p 0.63 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,064 alleles

Overall 0.000137% 2/1,454,780 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,064
European (non-Finnish)	8.48e-05%	1,179,934

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.Ala4Thr
Coding: c.10G>A
MANE Select: NM_004655
dbSNP: rs1175877868
Type: single nucleotide variant
Location: chr17:65558611 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.71 · 1 PDB
Residue 4: 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

Similar variants

AXIN2 p.Ala4Gly Uncertain significance ★★ ⚠ same residue
AXIN2 p.Ala4fs Pathogenic ★ same residue
AXIN2 p.Ala4= Likely benign ★ 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-ala4thr (accessed [today's date]).

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