Is APC p.Ser1028Arg (c.3084T>A) pathogenic?

APC p.Ser1028Arg (c.3084T>A) is classified Likely pathogenic in APC (ClinVar, Expert panel, 5 submitters; last evaluated 2023-02-25). AlphaMissense: likely pathogenic (0.9959); Absent from gnomAD v4.1; Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Ser1028Arg (c.3084T>A)?

APC p.Ser1028Arg (c.3084T>A) is associated with familial adenomatous polyposis 1, hereditary neoplastic syndrome (ClinVar).

How common is APC p.Ser1028Arg (c.3084T>A) in the general population?

APC p.Ser1028Arg (c.3084T>A) is absent from gnomAD v4.1 (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.Ser1028Arg (c.3084T>A)?

AlphaMissense predicts likely pathogenic (score 0.9959) — an in-silico prediction, not a clinical call.

APC p.Ser1028Arg

c.3084T>A · rs876660265 · VCV233215

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9959 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

familial adenomatous polyposis 1

ClinGen expert panel — InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Likely Pathogenic for familial adenomatous polyposis 1. Applied ACMG criteria (verbatim):

PM2_Supporting PP1_Moderate PS3_Supporting PM5_Supporting PS4_Moderate

Curation rationale (ClinGen, verbatim)

The c.3084T>A variant in APC is a missense variant predicted to cause the substitution of serine by arginine at amino acid position 1028 p.(Ser1028Arg). This variant has been reported in 6 probands meeting phenotypic criteria, resulting in a total phenotype score of 3 (PS4_Moderate; Ambry Genetics internal data). This variant has been reported to segregate with FAP in 3 meioses in 2 families (6 meiosis in total) (PP1_Moderate; Ambry Genetics internal data). This variant is demonstrated to increased β-catenin regulated transcription activity and decreased binding to β-catenin by surface plasmon resonance (PS3_Supporting, Barcelona internal data). Another missense variant c.3083G>T (p.Ser1028Ile) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancers/ Polyposis VCEP (PM5_Supporting). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4_Moderate, PP1_Moderate, PS3_Supporting, PM2_Supporting, PM5_Supporting (VCEP Specification version 1; date of approval: 12/12/2022).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9959	likely pathogenic ✓ concordant with ClinVar · top 5% in APC
REVEL	0.736	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,681 bp · p 0.023 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APC
Protein: p.Ser1028Arg
Coding: c.3084T>A
MANE Select: NM_000038
dbSNP: rs876660265
Type: single nucleotide variant
Location: chr5:112838678 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1028: the 'responsible for down-regulation through a process mediated by direct ubiquitination' region; the 'interaction with catenins' region; a turn

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.Ser1028Asn Likely pathogenic ★★★ same residue
APC p.Ser1028Ile Likely pathogenic ★★★ same residue
APC p.Ser1028= Benign/Likely benign ★★ same residue
APC p.Ser1028Cys Uncertain significance ★ ⚠ same residue
APC p.Ser1028Gly Uncertain significance ★ ⚠ same residue
APC p.Ser1028Thr Uncertain significance ★ ⚠ same residue
APC c.1312+3A>C Likely pathogenic ★★★ same condition
APC c.1312+3A>G 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-ser1028arg (accessed [today's date]).

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