Is APC2 p.Arg853Pro (c.2558G>C) pathogenic?

APC2 p.Arg853Pro (c.2558G>C) is classified Uncertain significance in APC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-28). AlphaMissense: likely pathogenic (0.9909); Very rare (popmax 0.000173%, nfe); Associated with APC2-related disorder.

What condition is associated with APC2 p.Arg853Pro (c.2558G>C)?

APC2 p.Arg853Pro (c.2558G>C) is associated with APC2-related disorder (ClinVar).

How common is APC2 p.Arg853Pro (c.2558G>C) in the general population?

APC2 p.Arg853Pro (c.2558G>C) is very rare (popmax 0.000173%, nfe) (gnomAD).

What do computational predictors say about APC2 p.Arg853Pro (c.2558G>C)?

AlphaMissense predicts likely pathogenic (score 0.9909) — an in-silico prediction, not a clinical call.

APC2 p.Arg853Pro

c.2558G>C · rs762097433 · VCV2631629

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000173%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

APC2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9909	likely pathogenic · top 4% in APC2
REVEL	0.61	indeterminate
SaProt	LLR -10.77	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.4, phastCons 1
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000173% European (non-Finnish) · 2/1,158,678 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000141% 2/1,414,786 alleles · very rare

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: APC2
Protein: p.Arg853Pro
Coding: c.2558G>C
MANE Select: NM_005883
dbSNP: rs762097433
Type: single nucleotide variant
Location: chr19:1465859 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 853: a UniProt-annotated variant site (in cdcbm10)

Full APC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

APC2-related disorder

Similar variants

APC2 p.Gln1000Lys Uncertain significance ★★ ⚠ same condition
APC2 p.Pro1253Ser Uncertain significance ★★ ⚠ same condition
APC2 p.Pro2066Ala Uncertain significance ★★ ⚠ same condition
APC2 p.Arg1602Trp Uncertain significance ★ ⚠ same condition
APC2 p.Leu283= Conflicting classifications of pathogenicity ★ same condition
APC2 p.Ser1861Asn Uncertain significance ★ ⚠ same condition
APC2 c.1638+1G>C Likely pathogenic same condition
APC2 p.Ala1705Gly Uncertain significance ⚠ 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/apc2-p-arg853pro (accessed [today's date]).

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