Is AXIN2 p.Arg671Pro (c.2012G>C) pathogenic?

AXIN2 p.Arg671Pro (c.2012G>C) is classified Conflicting classifications of pathogenicity in AXIN2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.1926); Ultra-rare (popmax 0.0418%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with AXIN2 p.Arg671Pro (c.2012G>C)?

AXIN2 p.Arg671Pro (c.2012G>C) is associated with hereditary neoplastic syndrome, oligodontia-cancer predisposition syndrome (ClinVar).

How common is AXIN2 p.Arg671Pro (c.2012G>C) in the general population?

AXIN2 p.Arg671Pro (c.2012G>C) is ultra-rare (popmax 0.0418%, amr) (gnomAD).

What do computational predictors say about AXIN2 p.Arg671Pro (c.2012G>C)?

AlphaMissense predicts likely benign (score 0.1926) — an in-silico prediction, not a clinical call.

AXIN2 p.Arg671Pro

c.2012G>C · rs765845684 · VCV240006

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1926 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0418%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1926	likely benign
REVEL	0.333	indeterminate
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 25 kb · p 0.011 · regional, not allelic
Overall
CADD	24.5	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 0.0418% Admixed American · 25/59,810 alleles

Filtering AF 0.029% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0248%

Overall 0.00192% 28/1,461,274 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0418%	2,392
Remaining individualsnot grpmax-eligible	0.0016%	62,440
European (non-Finnish)	0.00017%	589,953

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.Arg671Pro
Coding: c.2012G>C
MANE Select: NM_004655
dbSNP: rs765845684
Type: single nucleotide variant
Location: chr17:65536449 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.71 · 1 PDB
Residue 671: 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: oligodontia-cancer predisposition syndrome

Similar variants

AXIN2 p.Arg671His Uncertain significance ★★ ⚠ same residue
AXIN2 p.Arg671= Benign/Likely benign ★★ same residue
AXIN2 p.Arg671Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
AXIN2 p.Arg671Leu Uncertain significance ★ ⚠ same residue
AXIN2 p.Arg671_Arg675delinsCys Uncertain significance ★★ same residue
AXIN2 p.Arg671fs Pathogenic ★ 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-arg671pro (accessed [today's date]).

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