PPEF2

Chr 4

protein phosphatase with EF-hand domain 2

Also known as: PPP7CB

NCBI Gene: 5470 ENSG00000156194 UniProt: O14830 OMIM: 602256

The protein is a serine/threonine phosphatase with EF-hand calcium-binding motifs that is specifically expressed in photoreceptors and pineal gland, where it may dephosphorylate photoactivated rhodopsin and regulate phototransduction. Mutations cause autosomal recessive retinitis pigmentosa, resulting in progressive vision loss affecting the retina. The gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the serine/threonine protein phosphatase with EF-hand motif family. The protein contains a protein phosphatase catalytic domain, and at least two EF-hand calcium-binding motifs in its C terminus. Although its substrate(s) is unknown, the encoded protein, which is expressed specifically in photoreceptors and the pineal, has been suggested to play a role in the visual system. This gene shares high sequence similarity with the Drosophila retinal degeneration C (rdgC) gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.96

Clinical Summary— PPEF2

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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

112 VUS of 125 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?

0.96LOEUF

pLI 0.000

Z-score 1.73

OE 0.70 (0.52–0.96)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.04Z-score

OE missense 0.99 (0.92–1.08)

434 obs / 436.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.70 (0.52–0.96)

0≤0.351.4

Missense OE?0.99 (0.92–1.08)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 28 / 39.8Missense obs/exp: 434 / 436.6Syn Z: -0.68

This gene — mechanism propensity

0.6648th %ile

GOF

0.7126th %ile

LOF

0.2871th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

125 submitted variants in ClinVar

ClinVar

Classification Summary

VUS112

Likely Benign7

112

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	112	0	112
Likely Benign	4	3	7
Benign	0	0	0
Total	116	3	119

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap PPEF2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →