Is PAPPA2 p.Ser1450Pro (c.4348T>C) pathogenic?

PAPPA2 p.Ser1450Pro (c.4348T>C) is classified Uncertain significance in PAPPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: likely benign (0.219); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PAPPA2 p.Ser1450Pro (c.4348T>C)?

PAPPA2 p.Ser1450Pro (c.4348T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PAPPA2 p.Ser1450Pro (c.4348T>C) in the general population?

PAPPA2 p.Ser1450Pro (c.4348T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PAPPA2 p.Ser1450Pro (c.4348T>C)?

AlphaMissense predicts likely benign (score 0.219) — an in-silico prediction, not a clinical call.

PAPPA2 p.Ser1450Pro

c.4348T>C · rs2525790664 · VCV2300520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.219 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.219	likely benign
REVEL	0.394	indeterminate
SaProt	LLR -9.08	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 1.4	GERP -2.6, phastCons 0.1
Regional constraint	o/e 0.99	unconstrained · MANE · 141 kb · p 0.68 · regional, not allelic
Overall
CADD	18.22	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PAPPA2
Protein: p.Ser1450Pro
Coding: c.4348T>C
MANE Select: NM_020318
dbSNP: rs2525790664
Type: single nucleotide variant
Location: chr1:176769631 (GRCh38)
Gene constraint: LOEUF 0.549 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.65 · 1 PDB
Residue 1450: the sushi 1 domain; a disulfide bond; a UniProt-annotated variant site (in ssda)

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-ser1450pro (accessed [today's date]).

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