PPFIBP1

Chr 12AR

PPFIB scaffold protein 1

Also known as: L2, NEDSMBA, SGT2, hSGT2, hSgt2p

NCBI Gene: 8496ENSG00000110841UniProt: Q86W92

The protein encoded by this gene is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family. Liprins interact with members of LAR family of transmembrane protein tyrosine phosphatases, which are known to be important for axon guidance and mammary gland development. It has been proposed that liprins are multivalent proteins that form complex structures and act as scaffolds for the recruitment and anchoring of LAR family of tyrosine phosphatases. This protein was found to interact with S100A4, a calcium-binding protein related to tumor invasiveness and metastasis. In vitro experiment demonstrated that the interaction inhibited the phosphorylation of this protein by protein kinase C and protein kinase CK2. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalitiesMIM #620024
AR
222
ClinVar variants
47
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PPFIBP1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
47 Pathogenic / Likely Pathogenic· 149 VUS of 222 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.75LOEUF
pLI 0.000
Z-score 3.15
OE 0.57 (0.43–0.75)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.75Z-score
OE missense 0.91 (0.84–0.98)
482 obs / 530.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.57 (0.43–0.75)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.84–0.98)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.92
0≤1.21.6
LoF obs/exp: 35 / 61.8Missense obs/exp: 482 / 530.3Syn Z: 0.92

ClinVar Variant Classifications

222 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44
Likely Pathogenic3
VUS149
Likely Benign21
Benign2
Conflicting3
44
Pathogenic
3
Likely Pathogenic
149
VUS
21
Likely Benign
2
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
38
0
44
Likely Pathogenic
1
0
2
0
3
VUS
0
133
16
0
149
Likely Benign
0
8
9
4
21
Benign
0
1
1
0
2
Conflicting
—3
Total7142664222

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PPFIBP1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PPFIBP1-related neurodevelopmental disorder

strong
ARUndeterminedAbsent Gene Product, Altered Gene Product Structure, Decreased Gene Product Level
Dev. Disorders
G2P ↗
missense variantstop gained NMD triggeringframeshift variant NMD triggeringsplice acceptor variant NMD triggering

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities

MIM #620024

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genomic and phenotypic delineation of congenital microcephaly.
Shaheen R et al.·Genet Med
2019
A novel homozygous truncating variant in PPFIBP1 further delineates PPFIBP1-associated neurodevelopmental disorder.
Waqas A et al.·Int J Dev Neurosci
2023
Novel cancer gene discovery using a forward genetic screen in RCAS-PDGFB-driven gliomas.
Weishaupt H et al.·Neuro Oncol
2023
Epithelioid fibrous histiocytoma: molecular characterization of ALK fusion partners in 23 cases.
Dickson BC et al.·Mod Pathol
2018Cohort
Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing.
Selvanathan SP et al.·Proc Natl Acad Sci U S A
2015
Molecular Heterogeneity and Clinicopathologic Correlations in Inflammatory Myofibroblastic Tumors of the Urinary Bladder: A Study of 20 Cases With Predominant FN1::ALK Fusions and Novel Kinase Rearrangements.
Zhao M et al.·Am J Surg Pathol
2026Cohort
Challenges in Genomic Variant Interpretation Within Pakistani Populations due to Genomic Healthcare Inequalities.
Khalid Z et al.·Am J Med Genet A
2025
Inflammatory myofibroblastic tumour of the lung with a novel PPFIBP1-ALK fusion variant.
Yoshida A et al.·Histopathology
2013Case report
Molecular investigation of ALK-rearranged epithelioid fibrous histiocytomas identifies CLTC as a novel fusion partner and evidence of fusion-independent transcription activation.
Georgantzoglou N et al.·Genes Chromosomes Cancer
2022
Interstitial 12p Deletion Syndrome: Revised Minimal Critical Region and Review of the Literature.
Privitera F et al.·Genes (Basel)
2026Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools