Is APC2 p.Arg488His (c.1463G>A) pathogenic?

APC2 p.Arg488His (c.1463G>A) is classified Uncertain significance in APC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-17). AlphaMissense: likely benign (0.1142); Ultra-rare (popmax 0.0658%, mid); Associated with Inborn genetic diseases.

What condition is associated with APC2 p.Arg488His (c.1463G>A)?

APC2 p.Arg488His (c.1463G>A) is associated with Inborn genetic diseases (ClinVar).

How common is APC2 p.Arg488His (c.1463G>A) in the general population?

APC2 p.Arg488His (c.1463G>A) is ultra-rare (popmax 0.0658%, mid) (gnomAD).

What do computational predictors say about APC2 p.Arg488His (c.1463G>A)?

AlphaMissense predicts likely benign (score 0.1142) — an in-silico prediction, not a clinical call.

APC2 p.Arg488His

c.1463G>A · rs144538191 · VCV1010344

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1142 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1142	likely benign
REVEL	0.484	indeterminate
SaProt	LLR -8.95	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 5.7	GERP -2, phastCons 1
Overall
CADD	26.5	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 0.0658% Middle Eastern · 4/6,082 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0109% 176/1,612,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0658%	1,521
East Asian	0.029%	3,453
European (non-Finnish)	0.0125%	8,027
Remaining individualsnot grpmax-eligible	0.0112%	8,923
South Asian	0.00549%	18,216

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.Arg488His
Coding: c.1463G>A
MANE Select: NM_005883
dbSNP: rs144538191
Type: single nucleotide variant
Location: chr19:1460799 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 488: 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.Arg488= Likely benign ★ same residue
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

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-arg488his (accessed [today's date]).

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