Is APC p.Pro2158Arg (c.6473C>G) pathogenic?

APC p.Pro2158Arg (c.6473C>G) is classified Conflicting classifications of pathogenicity in APC (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-05-05). AlphaMissense: likely benign (0.2299); Ultra-rare (popmax 0.014%, nfe); Associated with classic or attenuated familial adenomatous polyposis.

What condition is associated with APC p.Pro2158Arg (c.6473C>G)?

APC p.Pro2158Arg (c.6473C>G) is associated with classic or attenuated familial adenomatous polyposis, hereditary neoplastic syndrome, familial adenomatous polyposis 1 (ClinVar).

How common is APC p.Pro2158Arg (c.6473C>G) in the general population?

APC p.Pro2158Arg (c.6473C>G) is ultra-rare (popmax 0.014%, nfe) (gnomAD).

What do computational predictors say about APC p.Pro2158Arg (c.6473C>G)?

AlphaMissense predicts likely benign (score 0.2299) — an in-silico prediction, not a clinical call.

APC p.Pro2158Arg

c.6473C>G · rs587779804 · VCV127313

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.2299 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

classic or attenuated familial adenomatous polyposis

Computational evidence

Protein change
AlphaMissense	0.2299	likely benign
REVEL	0.645	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 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 4,236 bp · p 0.00065 · regional, not allelic
Overall
CADD	25.2	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 0.014% European (non-Finnish) · 165/1,178,420 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0108% 174/1,612,082 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.014%	7,142
Remaining individualsnot grpmax-eligible	0.00961%	10,404
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,582
African / African-American	0.00267%	37,404

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.Pro2158Arg
Coding: c.6473C>G
MANE Select: NM_000038
dbSNP: rs587779804
Type: single nucleotide variant
Location: chr5:112842067 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2158: the 'disordered' region

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.Pro2158Leu Uncertain significance ★★ same residue
APC p.Pro2158= Benign/Likely benign ★★ same residue
APC p.Pro2158His Conflicting classifications of pathogenicity ★ same residue
APC p.Pro2158Ser Uncertain significance ★ ⚠ same residue
APC p.Pro2158Thr 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

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-pro2158arg (accessed [today's date]).

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