Is PAPPA2 p.Ala451Val (c.1352C>T) pathogenic?

PAPPA2 p.Ala451Val (c.1352C>T) is classified Conflicting classifications of pathogenicity in PAPPA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-06-04). AlphaMissense: likely benign (0.0644); Rare (popmax 0.736%, afr); Associated with Inborn genetic diseases.

What condition is associated with PAPPA2 p.Ala451Val (c.1352C>T)?

PAPPA2 p.Ala451Val (c.1352C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PAPPA2 p.Ala451Val (c.1352C>T) in the general population?

PAPPA2 p.Ala451Val (c.1352C>T) is rare (popmax 0.736%, afr) (gnomAD).

What do computational predictors say about PAPPA2 p.Ala451Val (c.1352C>T)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

PAPPA2 p.Ala451Val

c.1352C>T · VCV4130834

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.736%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -7.05	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 2.3	GERP -2.7, phastCons 0.94
Regional constraint	o/e 0.90	unconstrained · MANE · 143 kb · p 0.00023 · regional, not allelic
Overall
CADD	6.871	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 0.736% African / African-American · 552/75,044 alleles

Filtering AF 0.685% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.665%

Overall 0.0487% 786/1,614,180 alleles · rare exomes 451/1,461,886 · genomes 335/152,294 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.736%	136
Admixed American	0.27%	371
Remaining individualsnot grpmax-eligible	0.0544%	1,839
East Asian	0.00669%	14,958
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)	0.00288%	34,707

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.Ala451Val
Coding: c.1352C>T
MANE Select: NM_020318
Type: single nucleotide variant
Location: chr1:176594956 (GRCh38)
Gene constraint: LOEUF 0.549 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.65 · 1 PDB
Residue 451: 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.Ala451Gly Uncertain significance ★ ⚠ same residue
PAPPA2 p.Ala451Thr 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

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-ala451val (accessed [today's date]).

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