Is ALPP p.Leu522Pro (c.1565T>C) pathogenic?

ALPP p.Leu522Pro (c.1565T>C) is classified Uncertain significance in ALPP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: likely benign (0.1532); Very rare (popmax 0.00733%, nfe).

How common is ALPP p.Leu522Pro (c.1565T>C) in the general population?

ALPP p.Leu522Pro (c.1565T>C) is very rare (popmax 0.00733%, nfe) (gnomAD).

What do computational predictors say about ALPP p.Leu522Pro (c.1565T>C)?

AlphaMissense predicts likely benign (score 0.1532) — an in-silico prediction, not a clinical call.

ALPP p.Leu522Pro

c.1565T>C · rs369703872 · VCV2599450

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1532 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00733%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1532	likely benign
REVEL	0.531	indeterminate
SaProt	LLR -11.62	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.44
Regional constraint	o/e 0.92	unconstrained · MANE · 469 bp · p 0.33 · regional, not allelic
Overall
CADD	18.35	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 0.00733% European (non-Finnish) · 86/1,173,396 alleles

Filtering AF 0.00607% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0056%

Overall 0.00633% 101/1,594,530 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0243%	4,112
European (non-Finnish)grpmax	0.00733%	13,644

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ALPP
Protein: p.Leu522Pro
Coding: c.1565T>C
MANE Select: NM_001632
dbSNP: rs369703872
Type: single nucleotide variant
Location: chr2:232381752 (GRCh38)
Gene constraint: LOEUF 1.117 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.73 · 8 PDB

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

Similar variants

ALPP c.865+8C>T Likely benign ★★ same type
ALPP p.Ala176= Benign ★★ same type
ALPP p.Arg231Pro Benign ★★ same type
ALPP p.Arg36= Benign ★★ same type
ALPP p.Glu37Gln Benign ★★ same type
ALPP p.Gly233= Likely benign ★★ same type
ALPP p.Gly63= Likely benign ★★ same type
ALPP p.Phe331= Benign ★★ 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/alpp-p-leu522pro (accessed [today's date]).

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