Is APC p.Ala1316Pro (c.3946G>C) pathogenic?

APC p.Ala1316Pro (c.3946G>C) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-28). AlphaMissense: likely benign (0.0886); Very rare (popmax 0.00988%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Ala1316Pro (c.3946G>C)?

APC p.Ala1316Pro (c.3946G>C) is associated with hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Ala1316Pro (c.3946G>C) in the general population?

APC p.Ala1316Pro (c.3946G>C) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about APC p.Ala1316Pro (c.3946G>C)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

APC p.Ala1316Pro

c.3946G>C · rs761621587 · VCV824410

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.255	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.23	GERP -5.9
Regional constraint	o/e 1.09	unconstrained · MANE · 1,681 bp · p 0.023 · regional, not allelic
Overall
CADD	0.083	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 0.00988% South Asian · 9/91,088 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.000821% 12/1,461,872 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,121
Admixed American	0.00167%	60,024
European (non-Finnish)	0.000169%	590,012

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: APC
Protein: p.Ala1316Pro
Coding: c.3946G>C
MANE Select: NM_000038
dbSNP: rs761621587
Type: single nucleotide variant
Location: chr5:112839540 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1316: the 'responsible for down-regulation through a process mediated by direct ubiquitination' region; the 'disordered' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial adenomatous polyposis 1

Similar variants

APC p.Ala1316= Likely benign ★★ same residue
APC p.Ala1316Gly Uncertain significance ★ ⚠ same residue
APC p.Ala1316fs Pathogenic ★ same residue
APC c.1312+3A>C Likely pathogenic ★★★ same condition
APC c.1312+3A>G Pathogenic ★★★ same condition
APC c.1312+5G>A Likely pathogenic ★★★ same condition
APC c.1312+5G>C Likely pathogenic ★★★ same condition
APC c.1409-3T>G Likely pathogenic ★★★ 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/apc-p-ala1316pro (accessed [today's date]).

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