Is APLP2 p.Glu86Asp (c.258A>T) pathogenic?

APLP2 p.Glu86Asp (c.258A>T) is classified Uncertain significance in APLP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.1175); Ultra-rare (popmax 0.0246%, eas).

How common is APLP2 p.Glu86Asp (c.258A>T) in the general population?

APLP2 p.Glu86Asp (c.258A>T) is ultra-rare (popmax 0.0246%, eas) (gnomAD).

What do computational predictors say about APLP2 p.Glu86Asp (c.258A>T)?

AlphaMissense predicts likely benign (score 0.1175) — an in-silico prediction, not a clinical call.

APLP2 p.Glu86Asp

c.258A>T · rs139145033 · VCV3127873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1175 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0246%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1175	likely benign
REVEL	0.308	indeterminate
SaProt	LLR -6.25	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 0.71	GERP -2.8, phastCons 0.94
Regional constraint	o/e 1.00	unconstrained · MANE · 73 kb · p 0.93 · regional, not allelic
Overall
CADD	17.66	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 0.0246% East Asian · 11/44,794 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00452% 73/1,613,286 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0246%	4,072
Remaining individualsnot grpmax-eligible	0.00641%	15,611
European (non-Finnish)	0.00492%	20,339

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.Glu86Asp
Coding: c.258A>T
MANE Select: NM_001142276
dbSNP: rs139145033
Type: single nucleotide variant
Location: chr11:130109581 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.87 · 3 PDB
Residue 86: the e1 domain; the 'gfld subdomain' region

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

Similar variants

APLP2 p.Glu86Val 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-glu86asp (accessed [today's date]).

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