Is APC2 p.Pro404Arg (c.1211C>G) pathogenic?

APC2 p.Pro404Arg (c.1211C>G) is classified Uncertain significance in APC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-18). AlphaMissense: ambiguous (0.3915); Ultra-rare (popmax 0.0177%, mid); Associated with Inborn genetic diseases.

What condition is associated with APC2 p.Pro404Arg (c.1211C>G)?

APC2 p.Pro404Arg (c.1211C>G) is associated with Inborn genetic diseases (ClinVar).

How common is APC2 p.Pro404Arg (c.1211C>G) in the general population?

APC2 p.Pro404Arg (c.1211C>G) is ultra-rare (popmax 0.0177%, mid) (gnomAD).

What do computational predictors say about APC2 p.Pro404Arg (c.1211C>G)?

AlphaMissense predicts ambiguous (score 0.3915) — an in-silico prediction, not a clinical call.

APC2 p.Pro404Arg

c.1211C>G · rs141413463 · VCV2186636

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3915 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0177%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3915	ambiguous
REVEL	0.646	pathogenic-leaning
SaProt	LLR -11.46	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Overall
CADD	24.4	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 0.0177% Middle Eastern · 1/5,660 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000356% 5/1,403,624 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0177%	5,660
Remaining individualsnot grpmax-eligible	0.00166%	60,264
European (non-Finnish)	0.000261%	383,115

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.Pro404Arg
Coding: c.1211C>G
MANE Select: NM_005883
dbSNP: rs141413463
Type: single nucleotide variant
Location: chr19:1457968 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 404: 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.Pro404Leu Uncertain significance ★ 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-pro404arg (accessed [today's date]).

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