Is AXIN2 p.Glu392Gln (c.1174G>C) pathogenic?

AXIN2 p.Glu392Gln (c.1174G>C) is classified Uncertain significance in AXIN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-15). AlphaMissense: likely benign (0.1732); Very rare (popmax 8.47e-05%, nfe); Associated with oligodontia-cancer predisposition syndrome.

What condition is associated with AXIN2 p.Glu392Gln (c.1174G>C)?

AXIN2 p.Glu392Gln (c.1174G>C) is associated with oligodontia-cancer predisposition syndrome, hereditary neoplastic syndrome (ClinVar).

How common is AXIN2 p.Glu392Gln (c.1174G>C) in the general population?

AXIN2 p.Glu392Gln (c.1174G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AXIN2 p.Glu392Gln (c.1174G>C)?

AlphaMissense predicts likely benign (score 0.1732) — an in-silico prediction, not a clinical call.

AXIN2 p.Glu392Gln

c.1174G>C · rs765441834 · VCV644763

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

oligodontia-cancer predisposition syndrome

Computational evidence

Protein change
AlphaMissense	0.1732	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 25 kb · p 0.011 · regional, not allelic
Overall
CADD	27.4	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 8.47e-05% European (non-Finnish) · 1/1,180,040 alleles

Overall 6.84e-05% 1/1,461,880 alleles · very rare

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.Glu392Gln
Coding: c.1174G>C
MANE Select: NM_004655
dbSNP: rs765441834
Type: single nucleotide variant
Location: chr17:65538229 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.71 · 1 PDB
Residue 392: the 'interaction with gsk3b' region; the 'interaction with siah1 and siah2' 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

Also linked: hereditary neoplastic syndrome

Similar variants

AXIN2 p.Glu392Lys Uncertain significance ★★ ⚠ same residue
AXIN2 p.Glu392= Conflicting classifications of pathogenicity ★ same residue
AXIN2 p.Glu392Ala Uncertain significance ★ same residue
AXIN2 p.Glu392Asp 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

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-glu392gln (accessed [today's date]).

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