Is APC2 p.Ser1145Pro (c.3433T>C) pathogenic?

APC2 p.Ser1145Pro (c.3433T>C) is classified Uncertain significance in APC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-12). AlphaMissense: ambiguous (0.3531); Ultra-rare (popmax 0.0979%, amr); Associated with Inborn genetic diseases.

What condition is associated with APC2 p.Ser1145Pro (c.3433T>C)?

APC2 p.Ser1145Pro (c.3433T>C) is associated with Inborn genetic diseases (ClinVar).

How common is APC2 p.Ser1145Pro (c.3433T>C) in the general population?

APC2 p.Ser1145Pro (c.3433T>C) is ultra-rare (popmax 0.0979%, amr) (gnomAD).

What do computational predictors say about APC2 p.Ser1145Pro (c.3433T>C)?

AlphaMissense predicts ambiguous (score 0.3531) — an in-silico prediction, not a clinical call.

APC2 p.Ser1145Pro

c.3433T>C · rs766907324 · VCV1699588

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3531 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0979%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3531	ambiguous
REVEL	0.489	indeterminate
SaProt	LLR -7.07	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Overall
CADD	24.7	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 0.0979% Admixed American · 50/51,070 alleles

Filtering AF 0.0762% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0686%

Overall 0.00447% 69/1,542,412 alleles · ultra-rare exomes 51/1,390,204 · genomes 18/152,208 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0979%	1,021
Remaining individualsnot grpmax-eligible	0.0251%	3,980
African / African-American	0.00273%	36,565
European (non-Finnish)	0.000175%	571,419

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.Ser1145Pro
Coding: c.3433T>C
MANE Select: NM_005883
dbSNP: rs766907324
Type: single nucleotide variant
Location: chr19:1466734 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 1145: the '5 x 20 aa approximate repeat of f-x-v-e-x-t-p-x-c-f-s-r-x-s-s-l-s-s-l-s' region; the 'interaction with ctnnb1' region; 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-ser1145pro (accessed [today's date]).

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