Is PAPPA2 p.Asp729Asn (c.2185G>A) pathogenic?

PAPPA2 p.Asp729Asn (c.2185G>A) is classified Likely benign in PAPPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.0618); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with PAPPA2 p.Asp729Asn (c.2185G>A)?

PAPPA2 p.Asp729Asn (c.2185G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PAPPA2 p.Asp729Asn (c.2185G>A) in the general population?

PAPPA2 p.Asp729Asn (c.2185G>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about PAPPA2 p.Asp729Asn (c.2185G>A)?

AlphaMissense predicts likely benign (score 0.0618) — an in-silico prediction, not a clinical call.

PAPPA2 p.Asp729Asn

c.2185G>A · VCV4130830

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0618	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP -2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 143 kb · p 0.00023 · regional, not allelic
Overall
CADD	14.26	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 0.004% African / African-American · 3/75,016 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.000744% 12/1,613,966 alleles · very rare exomes 12/1,461,712 · genomes 0/152,254 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,005
Admixed American	0.00167%	60,028
South Asian	0.0011%	91,066
European (non-Finnish)	0.000593%	168,555

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.Asp729Asn
Coding: c.2185G>A
MANE Select: NM_020318
Type: single nucleotide variant
Location: chr1:176690184 (GRCh38)
Gene constraint: LOEUF 0.549 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.65 · 1 PDB
Residue 729: 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.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-asp729asn (accessed [today's date]).

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