Is APC p.Arg856Cys (c.2566C>T) pathogenic?

APC p.Arg856Cys (c.2566C>T) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-14). AlphaMissense: likely benign (0.3336); Very rare (popmax 0.00178%, nfe); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Arg856Cys (c.2566C>T)?

APC p.Arg856Cys (c.2566C>T) is associated with familial adenomatous polyposis 1, hereditary neoplastic syndrome, classic or attenuated familial adenomatous polyposis (ClinVar).

How common is APC p.Arg856Cys (c.2566C>T) in the general population?

APC p.Arg856Cys (c.2566C>T) is very rare (popmax 0.00178%, 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.Arg856Cys (c.2566C>T)?

AlphaMissense predicts likely benign (score 0.3336) — an in-silico prediction, not a clinical call.

APC p.Arg856Cys

c.2566C>T · rs566005215 · VCV469755

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.3336 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Conditions

familial adenomatous polyposis 1

Computational evidence

Protein change
AlphaMissense	0.3336	likely benign
REVEL	0.606	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.21, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,681 bp · p 0.023 · regional, not allelic
Overall
CADD	25.0	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

Grpmax group 0.00178% European (non-Finnish) · 21/1,180,026 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00167% 27/1,614,002 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)grpmax	0.00178%	56,192
Admixed American	0.00167%	60,002
African / African-American	0.00134%	74,900
South Asian	0.0011%	91,078

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg856Cys
Coding: c.2566C>T
MANE Select: NM_000038
dbSNP: rs566005215
Type: single nucleotide variant
Location: chr5:112838160 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 856: the 'disordered' region

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 classic or attenuated familial adenomatous polyposis

For Familial adenomatous polyposis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

APC p.Arg856Gly Uncertain significance ★★ same residue
APC p.Arg856His Uncertain significance ★★ same residue
APC p.Arg856Ser Uncertain significance ★★ same residue
APC p.Arg856= Benign/Likely 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-arg856cys (accessed [today's date]).

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