Is APC p.Tyr486= (c.1458T>C) pathogenic?

APC p.Tyr486= (c.1458T>C) is classified Benign in APC (ClinVar, Expert panel, 25 submitters; last evaluated 2023-02-19). Common (popmax 70.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Tyr486= (c.1458T>C)?

APC p.Tyr486= (c.1458T>C) is associated with familial adenomatous polyposis 1, colon carcinoma, hepatocellular carcinoma (ClinVar).

How is Familial adenomatous polyposis inherited?

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

APC p.Tyr486=

Q: How common is APC p.Tyr486= (c.1458T>C) in the general population?

APC p.Tyr486= (c.1458T>C) is common (popmax 70.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1458T>C · rs2229992 · VCV42238

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 25 submitters

gnomAD v4.1

Common

common (popmax 70.8%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

familial adenomatous polyposis 1

ClinGen expert panel — InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

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

BP7 BP4 BA1

Curation rationale (ClinGen, verbatim)

The c.1458T>C (p.Tyr486=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency (non-cancer) in gnomAD v2.1.1 is 69.75% in Latino/Admixed American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.1%) for BA1, and therefore meets this criterion (BA1). 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: BA1, BP4, BP7 (VCEP specifications Version 1.0, date of approval: 12/12/2022).

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.023	GERP -2, phastCons 0.92
Overall
CADD	7.126	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 70.8% East Asian · 31,718/44,814 alleles

Filtering AF 70.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 69.9%

Overall 57.7% 930,477/1,612,952 alleles · common exomes 857,202/1,460,910 · genomes 73,275/152,042 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	70.8%	1
Admixed American	67.3%	1
South Asian	63.9%	2
Amishnot grpmax-eligible	63%	2
European (non-Finnish)	59.1%	2
Remaining individualsnot grpmax-eligible	57.1%	2
Ashkenazi Jewishnot grpmax-eligible	56.2%	2
Middle Eastern	55.4%	2
Finnishnot grpmax-eligible	51.1%	2
African / African-American	19.9%	5

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.Tyr486=
Coding: c.1458T>C
MANE Select: NM_000038
dbSNP: rs2229992
Type: single nucleotide variant
Location: chr5:112827157 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 486: an α-helix

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: colon carcinoma hepatocellular carcinoma hereditary neoplastic syndrome gastric neoplasm familial colorectal cancer

For Familial adenomatous polyposis (Orphanet):

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

Similar variants

APC p.Tyr486Ter Pathogenic ★ same residue
APC p.Tyr486Cys Uncertain significance ★ same residue
APC p.Tyr486His Uncertain significance ★ ⚠ same residue
APC p.Tyr486Phe 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

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-tyr486 (accessed [today's date]).

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