PVALB

Chr 22

parvalbumin

Also known as: D22S749

NCBI Gene: 5816 ENSG00000100362 UniProt: P20472 OMIM: 168890

This gene encodes parvalbumin, a high-affinity calcium-binding protein involved in muscle relaxation after contraction. Mutations cause autosomal recessive congenital myopathy with cores and rods, presenting in infancy with hypotonia and muscle weakness. The gene shows tolerance to loss-of-function variants, consistent with the recessive inheritance pattern observed in affected patients.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a high affinity calcium ion-binding protein that is structurally and functionally similar to calmodulin and troponin C. The encoded protein is thought to be involved in muscle relaxation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.36

Clinical Summary— PVALB

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Population Constraint (gnomAD)

Low constraint (pLI 0.09) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.36LOEUF

pLI 0.087

Z-score 1.10

OE 0.44 (0.18–1.36)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.04Z-score

OE missense 0.99 (0.80–1.22)

61 obs / 61.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.18–1.36)

0≤0.351.4

Missense OE?0.99 (0.80–1.22)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 2 / 4.5Missense obs/exp: 61 / 61.8Syn Z: 0.42

This gene — mechanism propensity

0.80top 25%

GOF

0.7027th %ile

LOF

0.2679th %ile

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

DNprediction above median

GOFprediction 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.