Is APC p.Leu826Val (c.2476T>G) pathogenic?

APC p.Leu826Val (c.2476T>G) is classified Benign in APC (ClinVar, Expert panel, 15 submitters; last evaluated 2023-02-25). AlphaMissense: likely benign (0.0916); Rare (popmax 0.148%, afr); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Leu826Val (c.2476T>G)?

APC p.Leu826Val (c.2476T>G) is associated with familial adenomatous polyposis 1, gastric cancer, colorectal cancer (ClinVar).

How common is APC p.Leu826Val (c.2476T>G) in the general population?

APC p.Leu826Val (c.2476T>G) is rare (popmax 0.148%, afr) (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.Leu826Val (c.2476T>G)?

AlphaMissense predicts likely benign (score 0.0916) — an in-silico prediction, not a clinical call.

APC p.Leu826Val

c.2476T>G · rs145245264 · VCV142010

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.0916 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, afr)

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):

BP1 BA1

Curation rationale (ClinGen, verbatim)

The c.2476T>G variant in APC is a missense variant predicted to cause a substitution of leucine by valine at amino acid position 826 (p.Leu826Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.1576% in the non-cancer African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation threshold (>0.1%) for BA1, and therefore meets this criterion (BA1). Additionally, APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel as a gene for which primarily truncating variants are known to cause disease (BP1). Multiple lines of computational evidence suggest no splicing impact. In summary, this variant meets the criteria to be classified as Benign for FAP. ACMG/AMP criteria applied, as specified by the ClinGen/InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel: BA1, 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	0.0916	likely benign
REVEL	0.213	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 0.53	GERP 0.48, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,681 bp · p 0.023 · regional, not allelic
Overall
CADD	12.6	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 0.148% African / African-American · 111/75,066 alleles

Filtering AF 0.125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.117%

Overall 0.00712% 115/1,614,206 alleles · rare exomes 45/1,461,864 · genomes 70/152,342 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.148%	676
Admixed American	0.00333%	30,011
Remaining individualsnot grpmax-eligible	0.0032%	31,255

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.Leu826Val
Coding: c.2476T>G
MANE Select: NM_000038
dbSNP: rs145245264
Type: single nucleotide variant
Location: chr5:112838070 (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

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

Also linked: gastric cancer colorectal cancer hepatocellular carcinoma hereditary neoplastic syndrome gastric adenocarcinoma and proximal polyposis of the stomach 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.Leu826= Benign/Likely benign ★★ same residue
APC p.Leu826Trp Uncertain significance ★ same residue
APC p.Leu826fs 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-leu826val (accessed [today's date]).

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