Is PAPPA2 p.Pro847Arg (c.2540C>G) pathogenic?

PAPPA2 p.Pro847Arg (c.2540C>G) is classified Uncertain significance in PAPPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). AlphaMissense: likely pathogenic (0.8692); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PAPPA2 p.Pro847Arg (c.2540C>G)?

PAPPA2 p.Pro847Arg (c.2540C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PAPPA2 p.Pro847Arg (c.2540C>G) in the general population?

PAPPA2 p.Pro847Arg (c.2540C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PAPPA2 p.Pro847Arg (c.2540C>G)?

AlphaMissense predicts likely pathogenic (score 0.8692) — an in-silico prediction, not a clinical call.

PAPPA2 p.Pro847Arg

c.2540C>G · rs1660150918 · VCV3208488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8692 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8692	likely pathogenic
REVEL	0.505	indeterminate
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 143 kb · p 0.00023 · regional, not allelic
Overall
CADD	26.6	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 8.48e-05% European (non-Finnish) · 1/1,179,914 alleles

Overall 6.84e-05% 1/1,461,756 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: PAPPA2
Protein: p.Pro847Arg
Coding: c.2540C>G
MANE Select: NM_020318
dbSNP: rs1660150918
Type: single nucleotide variant
Location: chr1:176692234 (GRCh38)
Gene constraint: LOEUF 0.549 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.65 · 1 PDB

Full PAPPA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PAPPA2 p.Arg326His Uncertain significance ★★ ⚠ same condition
PAPPA2 p.Arg617His Uncertain significance ★★ ⚠ same condition
PAPPA2 p.Leu782Arg Uncertain significance ★★ ⚠ same condition
PAPPA2 p.Phe1025Leu Uncertain significance ★★ ⚠ same condition
PAPPA2 p.Ala12Glu Uncertain significance ★ ⚠ same condition
PAPPA2 p.Ala1367Val Uncertain significance ★ ⚠ same condition
PAPPA2 p.Ala1738Thr Uncertain significance ★ same condition
PAPPA2 p.Ala1749Val Uncertain significance ★ ⚠ same condition

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/pappa2-p-pro847arg (accessed [today's date]).

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