Is PPIB p.Asn75Ser (c.224A>G) pathogenic?

PPIB p.Asn75Ser (c.224A>G) is classified Uncertain significance in PPIB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-06-04). AlphaMissense: likely pathogenic (0.8966); Very rare (popmax 0.000763%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PPIB p.Asn75Ser (c.224A>G)?

PPIB p.Asn75Ser (c.224A>G) is associated with Inborn genetic diseases, osteogenesis imperfecta type 9 (ClinVar).

How common is PPIB p.Asn75Ser (c.224A>G) in the general population?

PPIB p.Asn75Ser (c.224A>G) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about PPIB p.Asn75Ser (c.224A>G)?

AlphaMissense predicts likely pathogenic (score 0.8966) — an in-silico prediction, not a clinical call.

PPIB p.Asn75Ser

c.224A>G · rs202087362 · VCV1343507

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8966	likely pathogenic
REVEL	0.627	indeterminate
SaProt	LLR -12.77	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 6,960 bp · p 0.77 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000763% European (non-Finnish) · 9/1,179,750 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00601% 97/1,613,740 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.247%	406
Remaining individualsnot grpmax-eligible	0.024%	4,165
European (non-Finnish)grpmax	0.000763%	131,083

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: PPIB
Protein: p.Asn75Ser
Coding: c.224A>G
MANE Select: NM_000942
dbSNP: rs202087362
Type: single nucleotide variant
Location: chr15:64162066 (GRCh38)
Gene constraint: LOEUF 1.104 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.98 · 8 PDB
Residue 75: an α-helix; the ppiase cyclophilin-type domain

Full PPIB 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

Also linked: osteogenesis imperfecta type 9

Similar variants

PPIB c.-91A>C Uncertain significance ★★ same condition
PPIB p.Arg7Ser Uncertain significance ★★ ⚠ same condition
PPIB p.Glu183Ala Uncertain significance ★★ ⚠ same condition
PPIB p.Gly39Trp Uncertain significance ★★ ⚠ same condition
PPIB p.Lys116Arg Uncertain significance ★★ ⚠ same condition
PPIB p.Lys45Arg Uncertain significance ★★ ⚠ same condition
PPIB p.Lys92Arg Uncertain significance ★★ ⚠ same condition
PPIB p.Phe100Leu 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/ppib-p-asn75ser (accessed [today's date]).

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