Is APC p.Leu488Pro (c.1463T>C) pathogenic?

APC p.Leu488Pro (c.1463T>C) is classified Uncertain significance in APC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-04). AlphaMissense: likely benign (0.3012); Very rare (popmax 0.00267%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with APC p.Leu488Pro (c.1463T>C)?

APC p.Leu488Pro (c.1463T>C) is associated with hereditary neoplastic syndrome, colon adenocarcinoma, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Leu488Pro (c.1463T>C) in the general population?

APC p.Leu488Pro (c.1463T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about APC p.Leu488Pro (c.1463T>C)?

AlphaMissense predicts likely benign (score 0.3012) — an in-silico prediction, not a clinical call.

APC p.Leu488Pro

c.1463T>C · rs368434773 · VCV559962

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3012 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3012	likely benign
REVEL	0.79	moderately pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 8,173 bp · p 0.36 · regional, not allelic
Overall
CADD	27.2	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 0.00267% African / African-American · 2/75,024 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000137% 2/1,461,496 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: APC
Protein: p.Leu488Pro
Coding: c.1463T>C
MANE Select: NM_000038
dbSNP: rs368434773
Type: single nucleotide variant
Location: chr5:112827162 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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: colon adenocarcinoma familial adenomatous polyposis 1

Similar variants

APC p.Leu488Phe Uncertain significance ★★ 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
APC c.1409-5A>G Likely pathogenic ★★★ same condition
APC c.1626+2T>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-leu488pro (accessed [today's date]).

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