Is APC p.Arg141Ser (c.423G>T) pathogenic?

APC p.Arg141Ser (c.423G>T) is classified Pathogenic in APC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-05-04). AlphaMissense: likely pathogenic (0.986); Very rare (popmax 8.67e-05%, nfe); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Arg141Ser (c.423G>T)?

APC p.Arg141Ser (c.423G>T) is associated with familial adenomatous polyposis 1, colon carcinoma (ClinVar).

How common is APC p.Arg141Ser (c.423G>T) in the general population?

APC p.Arg141Ser (c.423G>T) is very rare (popmax 8.67e-05%, nfe) (gnomAD).

How is Familial adenomatous polyposis inherited?

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

What do computational predictors say about APC p.Arg141Ser (c.423G>T)?

AlphaMissense predicts likely pathogenic (score 0.986) — an in-silico prediction, not a clinical call.

APC p.Arg141Ser

c.423G>T · rs863224458 · VCV216017

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.67e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial adenomatous polyposis 1

Computational evidence

Protein change
AlphaMissense	0.986	likely pathogenic ✓ concordant with ClinVar · top 8% in APC
REVEL	0.723	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	Δ0.71	acceptor loss at this position · masked 0 · deltas
Pangolin	Δ0.23	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.3	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.82 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.67e-05% European (non-Finnish) · 1/1,153,092 alleles

Overall 6.34e-05% 1/1,576,900 alleles · very rare exomes 1/1,425,464 · genomes 0/151,436 · joint denominator

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.Arg141Ser
Coding: c.423G>T
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: colon carcinoma

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.Arg141= Uncertain significance ★★ 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-arg141ser (accessed [today's date]).

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