Is ALPP p.Pro520Arg (c.1559C>G) pathogenic?

ALPP p.Pro520Arg (c.1559C>G) is classified Uncertain significance in ALPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: likely benign (0.1633); Very rare (popmax 0.00268%, afr).

How common is ALPP p.Pro520Arg (c.1559C>G) in the general population?

ALPP p.Pro520Arg (c.1559C>G) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about ALPP p.Pro520Arg (c.1559C>G)?

AlphaMissense predicts likely benign (score 0.1633) — an in-silico prediction, not a clinical call.

ALPP p.Pro520Arg

c.1559C>G · VCV4045280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1633 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1633	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR -8.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10
Regional constraint	o/e 0.92	unconstrained · MANE · 469 bp · p 0.33 · regional, not allelic
Overall
CADD	4.997	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 0.00268% African / African-American · 2/74,630 alleles

Filtering AF 0.000767% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000608%

Overall 0.00107% 17/1,596,170 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,315
European (non-Finnish)	0.00128%	78,263

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.Pro520Arg
Coding: c.1559C>G
MANE Select: NM_001632
Type: single nucleotide variant
Location: chr2:232381746 (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-pro520arg (accessed [today's date]).

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