Is AXIN2 p.Ser81Phe (c.242C>T) pathogenic?

AXIN2 p.Ser81Phe (c.242C>T) is classified Conflicting classifications of pathogenicity in AXIN2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.7964); Very rare (popmax 0.000255%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with AXIN2 p.Ser81Phe (c.242C>T)?

AXIN2 p.Ser81Phe (c.242C>T) is associated with hereditary neoplastic syndrome, oligodontia-cancer predisposition syndrome (ClinVar).

How common is AXIN2 p.Ser81Phe (c.242C>T) in the general population?

AXIN2 p.Ser81Phe (c.242C>T) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about AXIN2 p.Ser81Phe (c.242C>T)?

AlphaMissense predicts likely pathogenic (score 0.7964) — an in-silico prediction, not a clinical call.

AXIN2 p.Ser81Phe

c.242C>T · rs146238336 · VCV415219

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7964	likely pathogenic
REVEL	0.69	pathogenic-leaning
SaProt	LLR -11.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 25 kb · p 0.011 · regional, not allelic
Overall
CADD	32.0	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 0.000255% European (non-Finnish) · 3/1,177,496 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00373% 60/1,610,738 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0782%	1,279
Remaining individualsnot grpmax-eligible	0.0112%	8,903
European (non-Finnish)grpmax	0.000255%	392,499

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser81Phe
Coding: c.242C>T
MANE Select: NM_004655
dbSNP: rs146238336
Type: single nucleotide variant
Location: chr17:65558379 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.71 · 1 PDB
Residue 81: the rgs domain

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: oligodontia-cancer predisposition syndrome

Similar variants

AXIN2 p.Ser81= 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
AXIN2 c.816-1G>A Likely pathogenic ★★ same condition
AXIN2 p.Arg129Ter 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-ser81phe (accessed [today's date]).

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