Is APLP2 p.Phe599Leu (c.1797C>G) pathogenic?

APLP2 p.Phe599Leu (c.1797C>G) is classified Uncertain significance in APLP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-01). AlphaMissense: ambiguous (0.4156); Very rare (popmax 0.00983%, nfe).

How common is APLP2 p.Phe599Leu (c.1797C>G) in the general population?

APLP2 p.Phe599Leu (c.1797C>G) is very rare (popmax 0.00983%, nfe) (gnomAD).

What do computational predictors say about APLP2 p.Phe599Leu (c.1797C>G)?

AlphaMissense predicts ambiguous (score 0.4156) — an in-silico prediction, not a clinical call.

APLP2 p.Phe599Leu

c.1797C>G · rs368879297 · VCV2216267

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4156 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00983%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4156	ambiguous
REVEL	0.125	moderately benign-leaning
SaProt	LLR -5.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.35, phastCons 1
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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00983% European (non-Finnish) · 116/1,180,002 alleles

Filtering AF 0.00834% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00776%

Overall 0.00719% 116/1,612,500 alleles · very rare

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.Phe599Leu
Coding: c.1797C>G
MANE Select: NM_001142276
dbSNP: rs368879297
Type: single nucleotide variant
Location: chr11:130135675 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.87 · 3 PDB

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-phe599leu (accessed [today's date]).

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