Is PAPPA2 p.Arg900Gln (c.2699G>A) pathogenic?

PAPPA2 p.Arg900Gln (c.2699G>A) is classified Uncertain significance in PAPPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-29). AlphaMissense: likely benign (0.0769); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with PAPPA2 p.Arg900Gln (c.2699G>A)?

PAPPA2 p.Arg900Gln (c.2699G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PAPPA2 p.Arg900Gln (c.2699G>A) in the general population?

PAPPA2 p.Arg900Gln (c.2699G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about PAPPA2 p.Arg900Gln (c.2699G>A)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

PAPPA2 p.Arg900Gln

c.2699G>A · VCV3414005

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -1.99	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 2.8	GERP -5, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 143 kb · p 0.00023 · regional, not allelic
Overall
CADD	22.4	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 0.00446% East Asian · 2/44,862 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00118% 19/1,614,078 alleles · very rare exomes 16/1,461,838 · genomes 3/152,240 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,431
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0032%	31,255
African / African-American	0.00267%	37,513
Admixed American	0.00167%	60,014
Finnishnot grpmax-eligible	0.00156%	64,024
European (non-Finnish)	0.000847%	118,000

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.Arg900Gln
Coding: c.2699G>A
MANE Select: NM_020318
Type: single nucleotide variant
Location: chr1:176695812 (GRCh38)
Gene constraint: LOEUF 0.549 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.65 · 1 PDB
Residue 900: 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-arg900gln (accessed [today's date]).

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