Is PAPPA2 p.Cys20Ser (c.59G>C) pathogenic?

PAPPA2 p.Cys20Ser (c.59G>C) is classified Likely benign in PAPPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.0561); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with PAPPA2 p.Cys20Ser (c.59G>C)?

PAPPA2 p.Cys20Ser (c.59G>C) is associated with Inborn genetic diseases (ClinVar).

How common is PAPPA2 p.Cys20Ser (c.59G>C) in the general population?

PAPPA2 p.Cys20Ser (c.59G>C) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about PAPPA2 p.Cys20Ser (c.59G>C)?

AlphaMissense predicts likely benign (score 0.0561) — an in-silico prediction, not a clinical call.

PAPPA2 p.Cys20Ser

c.59G>C · VCV4626869

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0561 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0561	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -5.81	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 3.9	GERP 0.32, phastCons 0.76
Regional constraint	o/e 0.90	unconstrained · MANE · 143 kb · p 0.00023 · regional, not allelic
Overall
CADD	3.293	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 0.00534% African / African-American · 4/74,944 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,614,088 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.Cys20Ser
Coding: c.59G>C
MANE Select: NM_020318
Type: single nucleotide variant
Location: chr1:176556381 (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-cys20ser (accessed [today's date]).

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