Is APC p.Arg94Ser (c.280C>A) pathogenic?

APC p.Arg94Ser (c.280C>A) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.3011); Very rare (popmax 0.00669%, eas); Associated with ovarian cancer.

What condition is associated with APC p.Arg94Ser (c.280C>A)?

APC p.Arg94Ser (c.280C>A) is associated with ovarian cancer, hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Arg94Ser (c.280C>A) in the general population?

APC p.Arg94Ser (c.280C>A) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about APC p.Arg94Ser (c.280C>A)?

AlphaMissense predicts likely benign (score 0.3011) — an in-silico prediction, not a clinical call.

APC p.Arg94Ser

c.280C>A · rs550945533 · VCV371803

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.3011 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.3011	likely benign
REVEL	0.508	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	Δ0.28	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 6	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.82 · regional, not allelic
Overall
CADD	23.9	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 0.00669% East Asian · 3/44,872 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000496% 8/1,614,094 alleles · very rare exomes 4/1,461,852 · genomes 4/152,242 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,957
African / African-American	0.004%	25,006
European (non-Finnish)	0.000169%	590,005

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.Arg94Ser
Coding: c.280C>A
MANE Select: NM_000038
dbSNP: rs550945533
Type: single nucleotide variant
Location: chr5:112767248 (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

ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome familial adenomatous polyposis 1

Similar variants

APC p.Arg94Cys Uncertain significance ★★ same residue
APC p.Arg94Gly Uncertain significance ★★ same residue
APC p.Arg94His Uncertain significance ★★ same residue
APC p.Arg94= Benign/Likely benign ★★ same residue
APC p.Arg94Pro Uncertain significance ★ same residue
APC p.Arg94delinsLeuGluGluIleGlyHisHisHisSerGlnTer Pathogenic ★ same residue
APC p.Arg94fs Likely pathogenic ★ same residue
APC c.1312+3A>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-arg94ser (accessed [today's date]).

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