Is AXIN2 p.Pro740Ser (c.2218C>T) pathogenic?

AXIN2 p.Pro740Ser (c.2218C>T) is classified Conflicting classifications of pathogenicity in AXIN2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.0682); Ultra-rare (popmax 0.0454%, afr); Associated with oligodontia-cancer predisposition syndrome.

What condition is associated with AXIN2 p.Pro740Ser (c.2218C>T)?

AXIN2 p.Pro740Ser (c.2218C>T) is associated with oligodontia-cancer predisposition syndrome, colorectal cancer, hereditary neoplastic syndrome (ClinVar).

How common is AXIN2 p.Pro740Ser (c.2218C>T) in the general population?

AXIN2 p.Pro740Ser (c.2218C>T) is ultra-rare (popmax 0.0454%, afr) (gnomAD).

What do computational predictors say about AXIN2 p.Pro740Ser (c.2218C>T)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

AXIN2 p.Pro740Ser

c.2218C>T · rs370503213 · VCV422840

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0454%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

oligodontia-cancer predisposition syndrome

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -5.88	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 3.2	GERP -1.6, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 25 kb · p 0.011 · regional, not allelic
Overall
CADD	12.28	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 0.0454% African / African-American · 34/74,926 alleles

Filtering AF 0.0334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0292%

Overall 0.00285% 46/1,614,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0454%	2,204
Remaining individualsnot grpmax-eligible	0.0112%	8,927
South Asian	0.00329%	30,362
Admixed American	0.00167%	60,012
European (non-Finnish)	8.47e-05%	1,180,038

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.Pro740Ser
Coding: c.2218C>T
MANE Select: NM_004655
dbSNP: rs370503213
Type: single nucleotide variant
Location: chr17:65535645 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.71 · 1 PDB
Residue 740: 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

Also linked: colorectal cancer hereditary neoplastic syndrome

Similar variants

AXIN2 p.Pro740Arg Uncertain significance ★★ ⚠ same residue
AXIN2 p.Pro740Leu Uncertain significance ★★ ⚠ same residue
AXIN2 p.Pro740= Benign/Likely benign ★★ same residue
AXIN2 p.Pro740Ala Uncertain significance ★ ⚠ same residue
AXIN2 p.Pro740Gln Uncertain significance ★ ⚠ same residue
AXIN2 p.Pro740Thr Uncertain significance ★ ⚠ same residue
AXIN2 c.1060-1G>C Likely pathogenic ★★ same condition
AXIN2 c.1200+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-pro740ser (accessed [today's date]).

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