Is AXIN2 p.Pro25fs (c.74del) pathogenic?

AXIN2 p.Pro25fs (c.74del) is classified Pathogenic/Likely pathogenic in AXIN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-02). Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with AXIN2 p.Pro25fs (c.74del)?

AXIN2 p.Pro25fs (c.74del) is associated with hereditary neoplastic syndrome, colorectal cancer, oligodontia-cancer predisposition syndrome (ClinVar).

How common is AXIN2 p.Pro25fs (c.74del) in the general population?

AXIN2 p.Pro25fs (c.74del) is very rare (popmax 0.00133%, afr) (gnomAD).

AXIN2 p.Pro25fs

c.74del · rs746837986 · VCV2583406

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 2 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -13	GERP -4.2
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,930 alleles

Overall 0.000657% 1/152,178 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.Pro25fs
Coding: c.74del
MANE Select: NM_004655
dbSNP: rs746837986
Type: Deletion
Location: chr17:65558547 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.71 · 1 PDB
Residue 25: 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: colorectal cancer oligodontia-cancer predisposition syndrome

Similar variants

AXIN2 p.Pro25Leu Uncertain significance ★★ ⚠ same residue
AXIN2 p.Pro25Ser Uncertain significance ★ ⚠ same residue
AXIN2 p.Pro25= Likely benign ★ same residue
AXIN2 p.Ala417fs Pathogenic ★★ same condition
AXIN2 p.Ala492fs Pathogenic/Likely pathogenic ★★ same condition
AXIN2 p.Asn344fs Pathogenic ★★ same condition
AXIN2 p.Glu32fs Pathogenic/Likely pathogenic ★★ same condition
AXIN2 p.Gly546fs 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-pro25fs (accessed [today's date]).

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