PPFIBP1

Chr 12AR

PPFIB scaffold protein 1

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

NCBI Gene: 8496 ENSG00000110841 UniProt: Q86W92 OMIM: 603141

The protein encoded by PPFIBP1 is a member of the liprin family that acts as a scaffold for recruiting and anchoring LAR family tyrosine phosphatases and may regulate focal adhesion disassembly. Biallelic mutations cause autosomal recessive neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.751), suggesting some tolerance to functional disruption.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.751 OMIM phenotype

Clinical Summary— PPFIBP1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 140 VUS of 204 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.000

Z-score 3.15

OE 0.57 (0.43–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.75Z-score

OE missense 0.91 (0.84–0.98)

482 obs / 530.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.43–0.75)

0≤0.351.4

Missense OE?0.91 (0.84–0.98)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 35 / 61.8Missense obs/exp: 482 / 530.3Syn Z: 0.92

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPPFIBP1-related neurodevelopmental disorderOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7229th %ile

GOF

0.6053th %ile

LOF

0.4234th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

204 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic3

VUS140

Likely Benign17

Benign1

Conflicting1

Pathogenic

Likely Pathogenic

140

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	0	0	0	11
Likely Pathogenic	3	0	0	0	3
VUS	1	135	4	0	140
Likely Benign	0	8	4	5	17
Benign	0	1	0	0	1
Conflicting	—				1
Total	15	144	8	5	173

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

View in ClinVar →

36 pathogenic / likely-pathogenic (of 57) ClinVar copy-number / structural variants overlap PPFIBP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →