Is APLP2 p.Arg509Cys (c.1525C>T) pathogenic?

APLP2 p.Arg509Cys (c.1525C>T) is classified Uncertain significance in APLP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: ambiguous (0.5005); Very rare (popmax 0.00695%, nfe).

How common is APLP2 p.Arg509Cys (c.1525C>T) in the general population?

APLP2 p.Arg509Cys (c.1525C>T) is very rare (popmax 0.00695%, nfe) (gnomAD).

What do computational predictors say about APLP2 p.Arg509Cys (c.1525C>T)?

AlphaMissense predicts ambiguous (score 0.5005) — an in-silico prediction, not a clinical call.

APLP2 p.Arg509Cys

c.1525C>T · VCV3883882

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5005 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00695%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5005	ambiguous
REVEL	0.379	indeterminate
SaProt	LLR -14.51	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.93, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 73 kb · p 0.93 · regional, not allelic
Overall
CADD	32.0	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 0.00695% European (non-Finnish) · 82/1,180,050 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00551% 89/1,614,124 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00695%	14,391
East Asian	0.00668%	14,966
African / African-American	0.00267%	37,469
Admixed American	0.00167%	60,006
Finnishnot grpmax-eligible	0.00156%	64,046

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: APLP2
Protein: p.Arg509Cys
Coding: c.1525C>T
MANE Select: NM_001142276
Type: single nucleotide variant
Location: chr11:130130107 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.87 · 3 PDB
Residue 509: an α-helix; the e2 domain

Full APLP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APLP2 p.Val336Leu Uncertain significance ★★ ⚠ same type
APLP2 c.1837+1543A>G Uncertain significance ★ ⚠ same type
APLP2 c.1837+1550C>T Uncertain significance ★ ⚠ same type
APLP2 c.1837+1564C>A Uncertain significance ★ ⚠ same type
APLP2 c.1837+1564C>T Uncertain significance ★ ⚠ same type
APLP2 c.1837+1567A>G Uncertain significance ★ ⚠ same type
APLP2 c.1837+1571A>G Uncertain significance ★ ⚠ same type
APLP2 p.Ala244Thr 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/aplp2-p-arg509cys (accessed [today's date]).

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