Is PAPPA2 p.Pro1461= (c.4383C>T) pathogenic?

PAPPA2 p.Pro1461= (c.4383C>T) is classified Benign/Likely benign in PAPPA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-13). Rare (popmax 0.396%, nfe).

How common is PAPPA2 p.Pro1461= (c.4383C>T) in the general population?

PAPPA2 p.Pro1461= (c.4383C>T) is rare (popmax 0.396%, nfe) (gnomAD).

PAPPA2 p.Pro1461=

c.4383C>T · rs182946018 · VCV2639583

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.396%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.6	GERP -5.1
Overall
CADD	1.891	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.396% European (non-Finnish) · 4,675/1,179,952 alleles

Filtering AF 0.387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.383%

Overall 0.366% 5,914/1,613,912 alleles · rare exomes 5,488/1,461,710 · genomes 426/152,202 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.55%	64
Remaining individualsnot grpmax-eligible	0.483%	207
European (non-Finnish)grpmax	0.396%	252
Admixed American	0.382%	262
Middle Eastern	0.297%	337
South Asian	0.179%	559
African / African-American	0.072%	1,389
Finnishnot grpmax-eligible	0.0219%	4,573

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1461=
Coding: c.4383C>T
MANE Select: NM_020318
dbSNP: rs182946018
Type: single nucleotide variant
Location: chr1:176769666 (GRCh38)
Gene constraint: LOEUF 0.549 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.65 · 1 PDB
Residue 1461: the sushi 1 domain; a UniProt-annotated variant site (in ssda)

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

Similar variants

PAPPA2 p.Glu1126Ter Pathogenic ★★ same type
PAPPA2 p.Arg326His Uncertain significance ★★ ⚠ same type
PAPPA2 p.Arg617His Uncertain significance ★★ ⚠ same type
PAPPA2 p.Leu782Arg Uncertain significance ★★ ⚠ same type
PAPPA2 p.Phe1025Leu Uncertain significance ★★ ⚠ same type
PAPPA2 p.Pro1397Leu Uncertain significance ★★ ⚠ same type
PAPPA2 c.3366-16A>G Benign/Likely benign ★★ same type
PAPPA2 p.Ala1527Ser Benign/Likely benign ★★ same type

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-pro1461 (accessed [today's date]).

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