Is APC p.Val1822Asp (c.5465T>A) pathogenic?

APC p.Val1822Asp (c.5465T>A) is classified Benign in APC (ClinVar, Expert panel, 27 submitters; last evaluated 2023-02-26). AlphaMissense: likely benign (0.0463); Common (popmax 95.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Val1822Asp (c.5465T>A)?

APC p.Val1822Asp (c.5465T>A) is associated with familial adenomatous polyposis 1, hereditary neoplastic syndrome, classic familial adenomatous polyposis (ClinVar).

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.Val1822Asp (c.5465T>A)?

AlphaMissense predicts likely benign (score 0.0463) — an in-silico prediction, not a clinical call.

APC p.Val1822Asp

Q: How common is APC p.Val1822Asp (c.5465T>A) in the general population?

APC p.Val1822Asp (c.5465T>A) is common (popmax 95.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.5465T>A · rs459552 · VCV21030

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 27 submitters

AlphaMissense

likely benign

0.0463 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 95.9%, afr) — too common for a highly-penetrant pathogenic allele

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.5465T>A variant in APC is a missense variant predicted to cause the substitution of Valine by Asparagine at amino acid position 1822 (p.Val1822Asp). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9598 (23897/24898 alleles) in the African/African American population, which is higher than the ClinGen APC 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 and 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	0.0463	likely benign
REVEL	0.19	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 7	GERP -0.93, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 4,236 bp · p 0.00065 · regional, not allelic
Overall
CADD	12.61	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 95.9% African / African-American · 71,843/74,942 alleles

Filtering AF 95.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 95%

Overall 78.1% 1,257,991/1,611,172 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	95.9%	1
East Asian	90.4%	1
Admixed American	82.4%	1
Remaining individualsnot grpmax-eligible	79%	1
Middle Eastern	79%	1
Amishnot grpmax-eligible	78.2%	1
South Asian	78%	1
European (non-Finnish)	76.7%	1
Ashkenazi Jewishnot grpmax-eligible	76.6%	1
Finnishnot grpmax-eligible	69%	1

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.Val1822Asp
Coding: c.5465T>A
MANE Select: NM_000038
dbSNP: rs459552
Type: single nucleotide variant
Location: chr5:112841059 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1822: a UniProt-annotated variant site (in); 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: hereditary neoplastic syndrome classic familial adenomatous polyposis classic or attenuated familial adenomatous polyposis 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.Val1822Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
APC p.Val1822Ile Uncertain significance ★ same residue
APC p.Val1822= Likely benign ★ same residue
APC p.Val1822Glu 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-val1822asp (accessed [today's date]).

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