Is PAPPA2 p.Ser898Phe (c.2693C>T) pathogenic?

PAPPA2 p.Ser898Phe (c.2693C>T) is classified Uncertain significance in PAPPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). AlphaMissense: likely benign (0.1438); Ultra-rare (popmax 0.0245%, eas); Associated with Inborn genetic diseases.

What condition is associated with PAPPA2 p.Ser898Phe (c.2693C>T)?

PAPPA2 p.Ser898Phe (c.2693C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PAPPA2 p.Ser898Phe (c.2693C>T) in the general population?

PAPPA2 p.Ser898Phe (c.2693C>T) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about PAPPA2 p.Ser898Phe (c.2693C>T)?

AlphaMissense predicts likely benign (score 0.1438) — an in-silico prediction, not a clinical call.

PAPPA2 p.Ser898Phe

c.2693C>T · VCV3304274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1438 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1438	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -2.87	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 4.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 143 kb · p 0.00023 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0245% East Asian · 11/44,866 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000743% 12/1,614,092 alleles · ultra-rare exomes 12/1,461,854 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,079
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Ser898Phe
Coding: c.2693C>T
MANE Select: NM_020318
Type: single nucleotide variant
Location: chr1:176695806 (GRCh38)
Gene constraint: LOEUF 0.549 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.65 · 1 PDB
Residue 898: a UniProt-annotated variant site (in ssda)

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-ser898phe (accessed [today's date]).

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