Is APC p.Ser2674Pro (c.8020T>C) pathogenic?

APC p.Ser2674Pro (c.8020T>C) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-18). AlphaMissense: ambiguous (0.5458); Very rare (popmax 6.2e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Ser2674Pro (c.8020T>C)?

APC p.Ser2674Pro (c.8020T>C) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Ser2674Pro (c.8020T>C) in the general population?

APC p.Ser2674Pro (c.8020T>C) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about APC p.Ser2674Pro (c.8020T>C)?

AlphaMissense predicts ambiguous (score 0.5458) — an in-silico prediction, not a clinical call.

APC p.Ser2674Pro

c.8020T>C · rs1766624875 · VCV2677396

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5458 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5458	ambiguous
REVEL	0.486	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 7.9	GERP 2.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 4,236 bp · p 0.00065 · regional, not allelic
Overall
CADD	25.4	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 6.2e-05%

Overall 6.2e-05% 1/1,613,882 alleles · very rare exomes 1/1,461,756 · genomes 0/152,126 · 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.Ser2674Pro
Coding: c.8020T>C
MANE Select: NM_000038
dbSNP: rs1766624875
Type: single nucleotide variant
Location: chr5:112843614 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2674: a modified residue (phosphoserine); the 'basic region' region; the 'interaction with dlg1' region; the 'disordered' region; the 'interaction with mapre1' region

Full APC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial adenomatous polyposis 1

Similar variants

APC p.Ser2674Phe Uncertain significance ★ same residue
APC p.Ser2674= 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
APC c.1409-3T>G Likely pathogenic ★★★ same condition
APC c.1409-5A>G 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-ser2674pro (accessed [today's date]).

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