Is APC2 p.Pro261Ala (c.781C>G) pathogenic?

APC2 p.Pro261Ala (c.781C>G) is classified Benign in APC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.0833); Low-frequency (popmax 1.03%, sas).

How common is APC2 p.Pro261Ala (c.781C>G) in the general population?

APC2 p.Pro261Ala (c.781C>G) is low-frequency (popmax 1.03%, sas) (gnomAD).

What do computational predictors say about APC2 p.Pro261Ala (c.781C>G)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

APC2 p.Pro261Ala

c.781C>G · rs142402932 · VCV747055

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.03%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.389	indeterminate
SaProt	LLR -6.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP 0.039, phastCons 0.35
Overall
CADD	19.14	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 1.03% South Asian · 927/90,346 alleles

Filtering AF 0.971% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.949%

Overall 0.0717% 1,153/1,608,610 alleles · low-frequency exomes 1,098/1,456,380 · genomes 55/152,230 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.03%	97
Middle Eastern	0.461%	217
Remaining individualsnot grpmax-eligible	0.116%	864
Admixed American	0.0151%	6,635
European (non-Finnish)	0.00976%	10,246
East Asian	0.00447%	22,363
African / African-American	0.00401%	24,959

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.Pro261Ala
Coding: c.781C>G
MANE Select: NM_005883
dbSNP: rs142402932
Type: single nucleotide variant
Location: chr19:1456369 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 261: the 'disordered' region; a UniProt-annotated variant site (in cdcbm10)

Full APC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APC2 p.Ala1059Glu Uncertain significance ★★ ⚠ same type
APC2 p.Ala1103Thr Uncertain significance ★★ ⚠ same type
APC2 p.Ala1116Val Uncertain significance ★★ ⚠ same type
APC2 p.Ala126Ser Uncertain significance ★★ ⚠ same type
APC2 p.Ala1311Thr Uncertain significance ★★ ⚠ same type
APC2 p.Ala1359Val Uncertain significance ★★ ⚠ same type
APC2 p.Ala1438Thr Uncertain significance ★★ ⚠ same type
APC2 p.Ala1492Glu Uncertain significance ★★ ⚠ same type

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-pro261ala (accessed [today's date]).

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