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…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.84

LOEUF

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in PDIA5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 83

669 rare PASS variants

Rare truncating (LoF)

1 in 1,300

114 rare PASS variants

Rare synonymous (reference)

1 in 130

266 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PDIA5. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 1,700
South Asian	~43k	1 in 62	1 in 480
Remaining (unassigned)	~30k	1 in 61	1 in 1,300
European (Finnish)	~27k	1 in 310	1 in 570
Admixed American	~22k	1 in 74	1 in 470
African / African American	~21k	1 in 95	1 in 540
East Asian	~20k	1 in 79	1 in 440
Ashkenazi Jewish	~13k	1 in 470	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 87	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 17 coding exons well covered in gnomAD exomes; exons 1, 5, 17 marginal. Genomes: all 17.? see exons ↓