Is APC2 p.Arg1812Pro (c.5435G>C) pathogenic?

APC2 p.Arg1812Pro (c.5435G>C) is classified Uncertain significance in APC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.13); Very rare (popmax 0.00224%, amr); Associated with Inborn genetic diseases.

What condition is associated with APC2 p.Arg1812Pro (c.5435G>C)?

APC2 p.Arg1812Pro (c.5435G>C) is associated with Inborn genetic diseases (ClinVar).

How common is APC2 p.Arg1812Pro (c.5435G>C) in the general population?

APC2 p.Arg1812Pro (c.5435G>C) is very rare (popmax 0.00224%, amr) (gnomAD).

What do computational predictors say about APC2 p.Arg1812Pro (c.5435G>C)?

AlphaMissense predicts likely benign (score 0.13) — an in-silico prediction, not a clinical call.

APC2 p.Arg1812Pro

c.5435G>C · rs1555678951 · VCV2362488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.13 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.13	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -5.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.86, phastCons 0.99
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00224% Admixed American · 1/44,688 alleles

Overall 0.000133% 2/1,499,298 alleles · very rare exomes 2/1,347,204 · genomes 0/152,094 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00224%	44,688
South Asian	0.00124%	80,412

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.Arg1812Pro
Coding: c.5435G>C
MANE Select: NM_005883
dbSNP: rs1555678951
Type: single nucleotide variant
Location: chr19:1468736 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 1812: the 'disordered' region; a UniProt-annotated variant site (in cdcbm10)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APC2 p.Ala1059Glu Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1103Thr Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1116Val Uncertain significance ★★ ⚠ same condition
APC2 p.Ala126Ser Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1311Thr Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1359Val Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1438Thr Uncertain significance ★★ ⚠ same condition
APC2 p.Ala1492Glu 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-arg1812pro (accessed [today's date]).

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