Is APC p.Arg141= (c.423G>A) pathogenic?

APC p.Arg141= (c.423G>A) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-26). Very rare (popmax 0.00052%, nfe); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Arg141= (c.423G>A)?

APC p.Arg141= (c.423G>A) is associated with familial adenomatous polyposis 1, hereditary neoplastic syndrome (ClinVar).

How common is APC p.Arg141= (c.423G>A) in the general population?

APC p.Arg141= (c.423G>A) is very rare (popmax 0.00052%, 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.Arg141=

c.423G>A · rs863224458 · VCV1441632

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00052%, nfe)

Conditions

familial adenomatous polyposis 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.26	acceptor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.3	phastCons 1
Overall
CADD	13.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00052% European (non-Finnish) · 6/1,153,094 alleles

Filtering AF 0.000187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000123%

Overall 0.000421% 6/1,425,466 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: APC
Protein: p.Arg141=
Coding: c.423G>A
MANE Select: NM_000038
dbSNP: rs863224458
Type: single nucleotide variant
Location: chr5:112775629 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 141: 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

Also linked: hereditary neoplastic syndrome

For Familial adenomatous polyposis (Orphanet):

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

Similar variants

APC p.Arg141Lys Uncertain significance ★★★ same residue
APC p.Arg141Thr Uncertain significance ★★★ ⚠ same residue
APC p.Arg141Ser Pathogenic ★★ same residue
APC p.Arg141Gly Uncertain significance ★★ ⚠ same residue
APC p.Arg141fs Pathogenic ★★ same residue
APC c.1312+3A>C Likely pathogenic ★★★ same condition
APC c.1312+3A>G Pathogenic ★★★ same condition
APC c.1312+5G>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/apc-p-arg141 (accessed [today's date]).

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