Is APC p.Arg121Ser (c.363A>C) pathogenic?

APC p.Arg121Ser (c.363A>C) is classified Uncertain significance in APC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-03). AlphaMissense: likely pathogenic (0.698); Very rare (popmax 0.000254%, nfe); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Arg121Ser (c.363A>C)?

APC p.Arg121Ser (c.363A>C) is associated with familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Arg121Ser (c.363A>C) in the general population?

APC p.Arg121Ser (c.363A>C) is very rare (popmax 0.000254%, 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.Arg121Ser (c.363A>C)?

AlphaMissense predicts likely pathogenic (score 0.698) — an in-silico prediction, not a clinical call.

APC p.Arg121Ser

c.363A>C · VCV3635395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.698 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

familial adenomatous polyposis 1

Computational evidence

Protein change
AlphaMissense	0.698	likely pathogenic
REVEL	0.501	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.82 · regional, not allelic
Overall
CADD	23.3	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 0.000254% European (non-Finnish) · 3/1,180,016 alleles

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

Overall 0.000186% 3/1,614,154 alleles · very rare exomes 3/1,461,840 · genomes 0/152,314 · 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.Arg121Ser
Coding: c.363A>C
MANE Select: NM_000038
Type: single nucleotide variant
Location: chr5:112767331 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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.Arg121Lys Uncertain significance ★★ same residue
APC p.Arg121Ile Conflicting classifications of pathogenicity ★ same residue
APC p.Arg121Thr Uncertain significance ★ same residue
APC p.Arg121= Benign ★ 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
APC c.1312+5G>C 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-arg121ser (accessed [today's date]).

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