PPFIA1

Chr 11

PPFI scaffold protein A1

Also known as: LIP.1, LIP1, LIPRIN

NCBI Gene: 8500 ENSG00000131626 UniProt: Q13136

The encoded protein regulates focal adhesion disassembly and localizes receptor-like tyrosine phosphatases to specific plasma membrane sites, which is critical for cell-matrix interactions and axon guidance. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability and developmental delay. This gene is extremely intolerant to loss-of-function variants, indicating that proper protein function is essential for normal development.

ResearchSummary from RefSeq, 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. This protein binds to the intracellular membrane-distal phosphatase domain of tyrosine phosphatase LAR, and appears to localize LAR to cell focal adhesions. This interaction may regulate the disassembly of focal adhesion and thus help orchestrate cell-matrix interactions. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.07

LOEUF· LoF intol.

LOF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.07LOEUF

pLI 1.000

Z-score 7.69

OE 0.01 (0.00–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.06Z-score

OE missense 0.89 (0.83–0.95)

618 obs / 696.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.01 (0.00–0.07)

0≤0.351.4

Missense OE?0.89 (0.83–0.95)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 1 / 70.8Missense obs/exp: 618 / 696.8Syn Z: 0.83

Background carrier burden — how many people carry a rare variant somewhere in PPFIA1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 38

1,568 rare PASS variants

Rare truncating (LoF)

1 in 1,400

94 rare PASS variants

Rare synonymous (reference)

1 in 80

575 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PPFIA1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

Exome coverage (gnomAD): 23 of 26 coding exons well covered in gnomAD exomes; exons 5, 12, 25 marginal. Genomes: all 26.? see exons ↓