Is APC p.Ser1864Phe (c.5591C>T) pathogenic?

APC p.Ser1864Phe (c.5591C>T) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-08). AlphaMissense: likely pathogenic (0.9617); Very rare (popmax 8.48e-05%, nfe); Associated with classic or attenuated familial adenomatous polyposis.

How common is APC p.Ser1864Phe (c.5591C>T) in the general population?

APC p.Ser1864Phe (c.5591C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about APC p.Ser1864Phe (c.5591C>T)?

AlphaMissense predicts likely pathogenic (score 0.9617) — an in-silico prediction, not a clinical call.

APC p.Ser1864Phe

Q: What condition is associated with APC p.Ser1864Phe (c.5591C>T)?

APC p.Ser1864Phe (c.5591C>T) is associated with classic or attenuated familial adenomatous polyposis, familial adenomatous polyposis 1 (ClinVar).

c.5591C>T · rs1359257049 · VCV656009

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9617 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

classic or attenuated familial adenomatous polyposis

Computational evidence

Protein change
AlphaMissense	0.9617	likely pathogenic
REVEL	0.625	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 4,236 bp · p 0.00065 · regional, not allelic
Overall
CADD	27.1	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 8.48e-05% European (non-Finnish) · 1/1,179,870 alleles

Overall 6.2e-05% 1/1,613,720 alleles · very rare exomes 0/1,461,636 · genomes 1/152,084 · 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.Ser1864Phe
Coding: c.5591C>T
MANE Select: NM_000038
dbSNP: rs1359257049
Type: single nucleotide variant
Location: chr5:112841185 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1864: a modified residue (phosphoserine)

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

Disease context

classic or attenuated familial adenomatous polyposis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial adenomatous polyposis 1

Similar variants

APC p.Ser1864Cys Uncertain significance ★★ same residue
APC p.Ser1864= 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-ser1864phe (accessed [today's date]).

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