Is PPIB p.Ser21= (c.63C>A) pathogenic?

PPIB p.Ser21= (c.63C>A) is classified Benign in PPIB (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 18.9%, amr) — too common for a highly-penetrant pathogenic allele; Associated with osteogenesis imperfecta type 9.

What condition is associated with PPIB p.Ser21= (c.63C>A)?

PPIB p.Ser21= (c.63C>A) is associated with osteogenesis imperfecta type 9 (ClinVar).

PPIB p.Ser21=

Q: How common is PPIB p.Ser21= (c.63C>A) in the general population?

PPIB p.Ser21= (c.63C>A) is common (popmax 18.9%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.63C>A · rs4904 · VCV31849

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 18.9%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

osteogenesis imperfecta type 9

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.45	donor gain · deltas
Constraint at this position
Conservation	phyloP -0.49	GERP -3.5, phastCons 0.002
Overall
CADD	17.61	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 18.9% Admixed American · 11,321/59,876 alleles

Filtering AF 18.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.5%

Overall 2.81% 45,375/1,613,344 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	18.9%	5
Finnishnot grpmax-eligible	4.72%	21
East Asian	3.48%	29
Remaining individualsnot grpmax-eligible	2.63%	38
African / African-American	2.35%	43
Middle Eastern	2.27%	44
South Asian	2%	50
European (non-Finnish)	2%	50
Ashkenazi Jewishnot grpmax-eligible	1.91%	52

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.Ser21=
Coding: c.63C>A
MANE Select: NM_000942
dbSNP: rs4904
Type: single nucleotide variant
Location: chr15:64162924 (GRCh38)
Gene constraint: LOEUF 1.104 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.98 · 8 PDB

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

Disease context

osteogenesis imperfecta type 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPIB c.-91A>C Uncertain significance ★★ same condition
PPIB p.Asn75Ser Uncertain significance ★★ ⚠ same condition
PPIB p.Phe100Leu Uncertain significance ★★ ⚠ same condition
PPIB c.135+14C>T Likely benign ★★ same condition
PPIB c.249+19G>T Benign/Likely benign ★★ same condition
PPIB c.529-21G>A Benign ★★ same condition
PPIB p.Gly29Arg Benign/Likely benign ★★ same condition
PPIB p.Ile205= Likely benign ★★ 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-ser21 (accessed [today's date]).

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