Is APC p.Pro448Ala (c.1342C>G) pathogenic?

APC p.Pro448Ala (c.1342C>G) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-06-22). AlphaMissense: ambiguous (0.5228); Very rare (popmax 0.00401%, afr); Associated with classic or attenuated familial adenomatous polyposis.

What condition is associated with APC p.Pro448Ala (c.1342C>G)?

APC p.Pro448Ala (c.1342C>G) is associated with classic or attenuated familial adenomatous polyposis, hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Pro448Ala (c.1342C>G) in the general population?

APC p.Pro448Ala (c.1342C>G) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about APC p.Pro448Ala (c.1342C>G)?

AlphaMissense predicts ambiguous (score 0.5228) — an in-silico prediction, not a clinical call.

APC p.Pro448Ala

c.1342C>G · rs374195067 · VCV234001

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.5228 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

classic or attenuated familial adenomatous polyposis

Computational evidence

Protein change
AlphaMissense	0.5228	ambiguous
REVEL	0.313	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 8,173 bp · p 0.36 · regional, not allelic
Overall
CADD	24.9	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 0.00401% African / African-American · 3/74,832 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,612,982 alleles · very rare exomes 3/1,460,930 · genomes 1/152,052 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,944
European (non-Finnish)	8.48e-05%	1,179,512

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.Pro448Ala
Coding: c.1342C>G
MANE Select: NM_000038
dbSNP: rs374195067
Type: single nucleotide variant
Location: chr5:112821925 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 448: an α-helix

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

Disease context

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

Also linked: hereditary neoplastic syndrome familial adenomatous polyposis 1

Similar variants

APC p.Pro448Arg Uncertain significance ★★ ⚠ same residue
APC p.Pro448Leu Uncertain significance ★★ same residue
APC p.Pro448Thr Uncertain significance ★★ same residue
APC p.Pro448= Likely benign ★ 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-pro448ala (accessed [today's date]).

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