PDIA5

Chr 3

protein disulfide isomerase family A member 5

Also known as: PDIR

NCBI Gene: 10954 ENSG00000065485 UniProt: Q14554 OMIM: 616942

The encoded protein is a disulfide isomerase that catalyzes protein folding and thiol-disulfide interchange reactions in the endoplasmic reticulum, with three catalytically active thioredoxin domains and a binding site for the ER chaperone calreticulin. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy. This gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq

This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, three catalytically active thioredoxin (TRX) domains, a TRX-like domain, and a C-terminal ER-retention sequence. The N-terminal TRX-like domain is the primary binding site for the major ER chaperone calreticulin and possibly other proteins and substrates as well. Alternative splicing results in multiple protein- and non-protein-coding transcript variants. [provided by RefSeq, Dec 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.84

Clinical Summary— PDIA5

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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

83 VUS of 114 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.84LOEUF

pLI 0.000

Z-score 2.32

OE 0.58 (0.40–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.24Z-score

OE missense 0.96 (0.87–1.06)

283 obs / 294.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.58 (0.40–0.84)

0≤0.351.4

Missense OE?0.96 (0.87–1.06)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 20 / 34.7Missense obs/exp: 283 / 294.5Syn Z: -0.42

This gene — mechanism propensity

0.7325th %ile

GOF

0.6834th %ile

LOF

0.2385th %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.

ClinVar Variant Classifications

114 submitted variants in ClinVar

ClinVar

Classification Summary

VUS83

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	83	83
Likely Benign	2	2
Benign	0	0
Total	85	85

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap PDIA5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →