Is APLP2 p.Arg485Trp (c.1453C>T) pathogenic?

APLP2 p.Arg485Trp (c.1453C>T) is classified Uncertain significance in APLP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: ambiguous (0.5143); Ultra-rare (popmax 0.011%, sas).

How common is APLP2 p.Arg485Trp (c.1453C>T) in the general population?

APLP2 p.Arg485Trp (c.1453C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about APLP2 p.Arg485Trp (c.1453C>T)?

AlphaMissense predicts ambiguous (score 0.5143) — an in-silico prediction, not a clinical call.

APLP2 p.Arg485Trp

c.1453C>T · VCV4123805

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5143 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Computational evidence

Protein change
AlphaMissense	0.5143	ambiguous
REVEL	0.391	indeterminate
SaProt	LLR -13.68	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.81	GERP 0.98, phastCons 0.23
Regional constraint	o/e 1.00	unconstrained · MANE · 73 kb · p 0.93 · regional, not allelic
Overall
CADD	23.6	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 0.011% South Asian · 10/90,920 alleles

Filtering AF 0.00595% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00454%

Overall 0.00167% 27/1,612,692 alleles · ultra-rare exomes 26/1,460,474 · genomes 1/152,218 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,092
Remaining individualsnot grpmax-eligible	0.0016%	62,418
European (non-Finnish)	0.00136%	73,708

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.Arg485Trp
Coding: c.1453C>T
MANE Select: NM_001142276
Type: single nucleotide variant
Location: chr11:130129204 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.87 · 3 PDB
Residue 485: the e2 domain

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

Similar variants

APLP2 p.Arg485Gln Uncertain significance ★ ⚠ same residue
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

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-arg485trp (accessed [today's date]).

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