Is APC p.Arg45Pro (c.134G>C) pathogenic?

APC p.Arg45Pro (c.134G>C) is classified Uncertain significance in APC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-02). Very rare (popmax 0.00356%, nfe); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Arg45Pro (c.134G>C)?

APC p.Arg45Pro (c.134G>C) is associated with familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Arg45Pro (c.134G>C) in the general population?

APC p.Arg45Pro (c.134G>C) is very rare (popmax 0.00356%, nfe) (gnomAD).

How is Familial adenomatous polyposis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

APC p.Arg45Pro

c.134G>C · rs1004213568 · VCV537689

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Conditions

familial adenomatous polyposis 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.133	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.042, phastCons 0.14
Overall
CADD	13.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% European (non-Finnish) · 37/1,038,604 alleles

Filtering AF 0.00263% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00277% 38/1,370,096 alleles · very rare exomes 37/1,217,968 · genomes 1/152,128 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,070
Remaining individualsnot grpmax-eligible	0.00199%	50,370

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: APC
Protein: p.Arg45Pro
Coding: c.134G>C
MANE Select: NM_000038 · reported on NM_001127511
dbSNP: rs1004213568
Type: single nucleotide variant
Location: chr5:112707851 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 45: an α-helix

Full APC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial adenomatous polyposis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial adenomatous polyposis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

APC p.Arg45Cys Conflicting classifications of pathogenicity ★ same residue
APC p.Arg45Gly Uncertain significance ★ same residue
APC p.Arg45His Uncertain significance ★ same residue
APC p.Arg45Leu Uncertain significance ★ same residue
APC p.Arg45Ser Uncertain significance ★ same residue
APC p.Lys45= Uncertain significance ★ same residue
APC p.Lys45fs Pathogenic ★★ same residue
APC p.Lys45Thr Uncertain significance ★ same residue

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/apc-p-arg45pro (accessed [today's date]).

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