Is APC2 p.Arg1456Pro (c.4367G>C) pathogenic?

APC2 p.Arg1456Pro (c.4367G>C) is classified Benign in APC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.1258); Common (popmax 10.7%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about APC2 p.Arg1456Pro (c.4367G>C)?

AlphaMissense predicts likely benign (score 0.1258) — an in-silico prediction, not a clinical call.

APC2 p.Arg1456Pro

Q: How common is APC2 p.Arg1456Pro (c.4367G>C) in the general population?

APC2 p.Arg1456Pro (c.4367G>C) is common (popmax 10.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4367G>C · rs116169601 · VCV1533681

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1258 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.7%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1258	likely benign
REVEL	0.528	indeterminate
SaProt	LLR -5.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.44	GERP -1.8
Overall
CADD	9.162	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 10.7% African / African-American · 7,313/68,332 alleles

Filtering AF 10.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.4%

Overall 0.898% 13,291/1,479,544 alleles · common exomes 8,162/1,327,292 · genomes 5,129/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.7%	9
South Asian	3.6%	28
East Asian	2.68%	37
Remaining individualsnot grpmax-eligible	1.23%	81
Admixed American	0.935%	107
Middle Eastern	0.84%	119
Ashkenazi Jewishnot grpmax-eligible	0.255%	393
European (non-Finnish)	0.0888%	1,126
Finnishnot grpmax-eligible	0.0725%	1,380

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: APC2
Protein: p.Arg1456Pro
Coding: c.4367G>C
MANE Select: NM_005883
dbSNP: rs116169601
Type: single nucleotide variant
Location: chr19:1467668 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 1456: the '5 x 20 aa approximate repeat of f-x-v-e-x-t-p-x-c-f-s-r-x-s-s-l-s-s-l-s' region; the 'interaction with ctnnb1' region; the 'disordered' region; a UniProt-annotated variant site (in cdcbm10)

Full APC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APC2 p.Arg1456Gln Uncertain significance ★ ⚠ same residue
APC2 p.Ala1059Glu Uncertain significance ★★ ⚠ same type
APC2 p.Ala1103Thr Uncertain significance ★★ ⚠ same type
APC2 p.Ala1116Val Uncertain significance ★★ ⚠ same type
APC2 p.Ala126Ser Uncertain significance ★★ ⚠ same type
APC2 p.Ala1311Thr Uncertain significance ★★ ⚠ same type
APC2 p.Ala1359Val Uncertain significance ★★ ⚠ same type
APC2 p.Ala1438Thr Uncertain significance ★★ ⚠ same type

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/apc2-p-arg1456pro (accessed [today's date]).

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