Is PPIB p.Met9Lys (c.26T>A) pathogenic?

PPIB p.Met9Lys (c.26T>A) is classified Likely pathogenic in PPIB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-24). AlphaMissense: likely benign (0.1673); Very rare (popmax 0.00447%, eas); Associated with osteogenesis imperfecta.

What condition is associated with PPIB p.Met9Lys (c.26T>A)?

PPIB p.Met9Lys (c.26T>A) is associated with osteogenesis imperfecta (ClinVar).

How common is PPIB p.Met9Lys (c.26T>A) in the general population?

PPIB p.Met9Lys (c.26T>A) is very rare (popmax 0.00447%, eas) (gnomAD).

How is Osteogenesis imperfecta inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PPIB p.Met9Lys (c.26T>A)?

AlphaMissense predicts likely benign (score 0.1673) — an in-silico prediction, not a clinical call.

PPIB p.Met9Lys

c.26T>A · VCV3339830

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

osteogenesis imperfecta

Computational evidence

Protein change
AlphaMissense	0.1673	likely benign ⚠ discordant with ClinVar
REVEL	0.374	indeterminate
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 6,960 bp · p 0.77 · regional, not allelic
Overall
CADD	24.8	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 0.00447% East Asian · 2/44,724 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000124% 2/1,611,146 alleles · very rare exomes 2/1,459,000 · genomes 0/152,146 · joint denominator

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.Met9Lys
Coding: c.26T>A
MANE Select: NM_000942
Type: single nucleotide variant
Location: chr15:64162961 (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 9: a UniProt-annotated variant site (in oi9; patients have white sclerae, normal dentition, no rhizomelia or severe deformity of long bones)

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

Disease context

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

For Osteogenesis imperfecta (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Worldwide)

Similar variants

PPIB p.Met9Val Likely pathogenic ★ ⚠ same residue
PPIB p.Met9Arg Uncertain significance ★ ⚠ same residue
PPIB p.Phe100Leu Uncertain significance ★★ ⚠ same condition
PPIB p.Thr108= Benign ★★ same condition
PPIB p.His166Pro Likely pathogenic ★ same condition
PPIB c.-8G>C Uncertain significance ★ same condition
PPIB c.-9C>G Conflicting classifications of pathogenicity ★ same condition
PPIB p.Arg95His 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-met9lys (accessed [today's date]).

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