Is APC2 p.Pro409Leu (c.1226C>T) pathogenic?

APC2 p.Pro409Leu (c.1226C>T) is classified Uncertain significance in APC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-09). AlphaMissense: likely pathogenic (0.8801); Ultra-rare (popmax 0.0926%, amr); Associated with Inborn genetic diseases.

What condition is associated with APC2 p.Pro409Leu (c.1226C>T)?

APC2 p.Pro409Leu (c.1226C>T) is associated with Inborn genetic diseases (ClinVar).

How common is APC2 p.Pro409Leu (c.1226C>T) in the general population?

APC2 p.Pro409Leu (c.1226C>T) is ultra-rare (popmax 0.0926%, amr) (gnomAD).

What do computational predictors say about APC2 p.Pro409Leu (c.1226C>T)?

AlphaMissense predicts likely pathogenic (score 0.8801) — an in-silico prediction, not a clinical call.

APC2 p.Pro409Leu

c.1226C>T · rs150835778 · VCV2071300

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8801 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0926%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8801	likely pathogenic
REVEL	0.346	indeterminate
SaProt	LLR -9.00	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -3.8, phastCons 1
Overall
CADD	25.7	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 0.0926% Admixed American · 48/51,832 alleles

Filtering AF 0.0717% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0643%

Overall 0.0175% 273/1,561,194 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0926%	1,080
Middle Eastern	0.0341%	2,930
Remaining individualsnot grpmax-eligible	0.0215%	4,654
European (non-Finnish)	0.0177%	5,646
African / African-American	0.00405%	24,670
South Asian	0.00354%	28,267

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.Pro409Leu
Coding: c.1226C>T
MANE Select: NM_005883
dbSNP: rs150835778
Type: single nucleotide variant
Location: chr19:1457983 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 409: 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.Pro409= 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-pro409leu (accessed [today's date]).

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