Is PAPPA2 p.Pro1657Arg (c.4970C>G) pathogenic?

PAPPA2 p.Pro1657Arg (c.4970C>G) is classified Likely benign in PAPPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-09). AlphaMissense: likely benign (0.0768); Low-frequency (popmax 3.84%, sas).

How common is PAPPA2 p.Pro1657Arg (c.4970C>G) in the general population?

PAPPA2 p.Pro1657Arg (c.4970C>G) is low-frequency (popmax 3.84%, sas) (gnomAD).

What do computational predictors say about PAPPA2 p.Pro1657Arg (c.4970C>G)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

PAPPA2 p.Pro1657Arg

c.4970C>G · VCV4853380

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.84%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -8.57	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 2.6	GERP 1.4, phastCons 0.025
Regional constraint	o/e 0.99	unconstrained · MANE · 141 kb · p 0.68 · regional, not allelic
Overall
CADD	17.76	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 3.84% South Asian · 3,499/91,060 alleles

Filtering AF 3.74% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.69%

Overall 0.815% 13,159/1,613,808 alleles · low-frequency exomes 11,964/1,461,610 · genomes 1,195/152,198 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	4.97%	20
South Asiangrpmax	3.84%	26
Middle Eastern	3.2%	31
Admixed American	1.96%	51
Remaining individualsnot grpmax-eligible	1.14%	88
Amishnot grpmax-eligible	0.987%	101
Finnishnot grpmax-eligible	0.841%	119
European (non-Finnish)	0.458%	218
African / African-American	0.204%	490
East Asian	0.00669%	14,951

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.Pro1657Arg
Coding: c.4970C>G
MANE Select: NM_020318
Type: single nucleotide variant
Location: chr1:176791432 (GRCh38)
Gene constraint: LOEUF 0.549 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.65 · 1 PDB
Residue 1657: the sushi 5 domain; a UniProt-annotated variant site (in ssda); a UniProt-annotated variant site (in)

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

Similar variants

PAPPA2 p.Pro1657Ala Uncertain significance ★ ⚠ same residue
PAPPA2 p.Pro1657Thr Uncertain significance ★ ⚠ same residue
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

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-pro1657arg (accessed [today's date]).

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