Is APC2 p.Ser1581Pro (c.4741T>C) pathogenic?

APC2 p.Ser1581Pro (c.4741T>C) is classified Uncertain significance in APC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-10). AlphaMissense: likely benign (0.3116); Very rare (popmax 0.000683%, nfe); Associated with Inborn genetic diseases.

What condition is associated with APC2 p.Ser1581Pro (c.4741T>C)?

APC2 p.Ser1581Pro (c.4741T>C) is associated with Inborn genetic diseases (ClinVar).

How common is APC2 p.Ser1581Pro (c.4741T>C) in the general population?

APC2 p.Ser1581Pro (c.4741T>C) is very rare (popmax 0.000683%, nfe) (gnomAD).

What do computational predictors say about APC2 p.Ser1581Pro (c.4741T>C)?

AlphaMissense predicts likely benign (score 0.3116) — an in-silico prediction, not a clinical call.

APC2 p.Ser1581Pro

c.4741T>C · rs1490906589 · VCV1707065

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3116 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000683%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3116	likely benign
REVEL	0.827	moderately pathogenic-leaning
SaProt	LLR -7.91	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.74, phastCons 1
Overall
CADD	27.0	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 0.000683% European (non-Finnish) · 8/1,172,082 alleles

Filtering AF 0.000294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.000507% 8/1,579,146 alleles · very rare

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.Ser1581Pro
Coding: c.4741T>C
MANE Select: NM_005883
dbSNP: rs1490906589
Type: single nucleotide variant
Location: chr19:1468042 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 1581: 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-ser1581pro (accessed [today's date]).

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