Is PAPPA2 p.Arg548Cys (c.1642C>T) pathogenic?

PAPPA2 p.Arg548Cys (c.1642C>T) is classified Uncertain significance in PAPPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-11). AlphaMissense: likely benign (0.1058); Very rare (popmax 0.00449%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PAPPA2 p.Arg548Cys (c.1642C>T)?

PAPPA2 p.Arg548Cys (c.1642C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PAPPA2 p.Arg548Cys (c.1642C>T) in the general population?

PAPPA2 p.Arg548Cys (c.1642C>T) is very rare (popmax 0.00449%, nfe) (gnomAD).

What do computational predictors say about PAPPA2 p.Arg548Cys (c.1642C>T)?

AlphaMissense predicts likely benign (score 0.1058) — an in-silico prediction, not a clinical call.

PAPPA2 p.Arg548Cys

c.1642C>T · rs868766303 · VCV2289270

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1058 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00449%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1058	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -11.56	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.43	GERP -3.6
Regional constraint	o/e 0.90	unconstrained · MANE · 143 kb · p 0.00023 · regional, not allelic
Overall
CADD	7.204	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 0.00449% European (non-Finnish) · 53/1,180,042 alleles

Filtering AF 0.0035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00318%

Overall 0.00353% 57/1,614,082 alleles · very rare exomes 52/1,461,892 · genomes 5/152,190 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00449%	22,265
East Asian	0.00223%	44,894
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00133%	74,936
South Asian	0.0011%	91,088

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.Arg548Cys
Coding: c.1642C>T
MANE Select: NM_020318
dbSNP: rs868766303
Type: single nucleotide variant
Location: chr1:176595246 (GRCh38)
Gene constraint: LOEUF 0.549 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.65 · 1 PDB
Residue 548: the 'metalloprotease' region; an α-helix

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.Arg548His Uncertain significance ★ ⚠ same residue
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

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-arg548cys (accessed [today's date]).

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