Is APC2 p.Arg1539Pro (c.4616G>C) pathogenic?

APC2 p.Arg1539Pro (c.4616G>C) is classified Uncertain significance in APC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-08). AlphaMissense: likely benign (0.1614); Rare (popmax 0.185%, mid); Associated with intellectual developmental disorder, autosomal recessive 74.

What condition is associated with APC2 p.Arg1539Pro (c.4616G>C)?

APC2 p.Arg1539Pro (c.4616G>C) is associated with intellectual developmental disorder, autosomal recessive 74, cortical dysplasia, complex, with other brain malformations 10 (ClinVar).

How common is APC2 p.Arg1539Pro (c.4616G>C) in the general population?

APC2 p.Arg1539Pro (c.4616G>C) is rare (popmax 0.185%, mid) (gnomAD).

What do computational predictors say about APC2 p.Arg1539Pro (c.4616G>C)?

AlphaMissense predicts likely benign (score 0.1614) — an in-silico prediction, not a clinical call.

APC2 p.Arg1539Pro

c.4616G>C · rs367655515 · VCV1028956

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1614 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.185%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

intellectual developmental disorder, autosomal recessive 74

Computational evidence

Protein change
AlphaMissense	0.1614	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -0.48, phastCons 0.28
Overall
CADD	17.61	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.185% Middle Eastern · 11/5,950 alleles

Filtering AF 0.104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0801%

Overall 0.0119% 188/1,584,240 alleles · rare exomes 177/1,432,070 · genomes 11/152,170 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.185%	541
South Asian	0.0638%	1,567
Remaining individualsnot grpmax-eligible	0.0179%	5,596
European (non-Finnish)	0.00895%	11,178
Admixed American	0.00677%	14,782

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.Arg1539Pro
Coding: c.4616G>C
MANE Select: NM_005883
dbSNP: rs367655515
Type: single nucleotide variant
Location: chr19:1467917 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.87
Residue 1539: 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

Disease context

intellectual developmental disorder, autosomal recessive 74 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cortical dysplasia, complex, with other brain malformations 10

Similar variants

APC2 p.Arg1539Gln Uncertain significance ★ ⚠ same residue
APC2 p.Ala1703Glu Uncertain significance ★★ ⚠ same condition
APC2 p.Ala791Val Uncertain significance ★★ ⚠ same condition
APC2 p.Arg1081Gly Uncertain significance ★★ ⚠ same condition
APC2 p.Arg1650His Uncertain significance ★★ ⚠ same condition
APC2 p.Arg1708Leu Uncertain significance ★★ ⚠ same condition
APC2 p.Gly1007Ser Uncertain significance ★★ ⚠ same condition
APC2 p.Gly1511Ser Uncertain significance ★★ ⚠ 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/apc2-p-arg1539pro (accessed [today's date]).

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