Is APC p.Ala239Pro (c.715G>C) pathogenic?

APC p.Ala239Pro (c.715G>C) is classified Benign in APC (ClinVar, Expert panel, 8 submitters; last evaluated 2023-02-18). AlphaMissense: likely benign (0.0809); Ultra-rare (popmax 0.0134%, eas); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Ala239Pro (c.715G>C)?

APC p.Ala239Pro (c.715G>C) is associated with familial adenomatous polyposis 1, ovarian cancer, hereditary neoplastic syndrome (ClinVar).

How common is APC p.Ala239Pro (c.715G>C) in the general population?

APC p.Ala239Pro (c.715G>C) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

How is Familial adenomatous polyposis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about APC p.Ala239Pro (c.715G>C)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

APC p.Ala239Pro

c.715G>C · rs777760565 · VCV220329

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial adenomatous polyposis 1

ClinGen expert panel — InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Benign for familial adenomatous polyposis 1. Applied ACMG criteria (verbatim):

BS2 BS1 BP1

Curation rationale (ClinGen, verbatim)

The c.715G>C variant in APC is a missense variant predicted to cause substitution of alanine by proline at amino acid 239 (p.Ala239Pro). This variant has been observed in ≥ 35 heterozygous individuals with no features or family history of FAP, worth ≥ 10 healthy individual points (BS2; Ambry, Invitae internal data). The highest allele frequency of this variant in gnomAD v2.1.1 (non-cancer) is 0.0002269 in East Asian population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.00001) for BS1 (BS1). Finally, APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS1, BS2, BP1. (VCEP specifications version 1; date of approval 12/12/2022).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 61 kb · p 0.82 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,666 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.000372% 6/1,612,386 alleles · ultra-rare exomes 5/1,460,092 · genomes 1/152,294 · joint denominator

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.Ala239Pro
Coding: c.715G>C
MANE Select: NM_000038
dbSNP: rs777760565
Type: single nucleotide variant
Location: chr5:112792515 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 239: the 'disordered' region

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

Disease context

familial adenomatous polyposis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ovarian cancer hereditary neoplastic syndrome classic or attenuated familial adenomatous polyposis

For Familial adenomatous polyposis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

APC p.Ala239Gly Uncertain significance ★★ ⚠ same residue
APC p.Ala239Ser Uncertain significance ★★ ⚠ same residue
APC p.Ala239Thr Uncertain significance ★★ ⚠ same residue
APC p.Ala239Val Uncertain significance ★ ⚠ same residue
APC p.Ala239= Likely benign ★ same residue
APC p.Ala239fs Pathogenic ★ same residue
APC c.1312+3A>C Likely pathogenic ★★★ same condition
APC c.1312+3A>G 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-ala239pro (accessed [today's date]).

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