PDIA3

Chr 15

protein disulfide isomerase family A member 3

Also known as: ER60, ERp57, ERp60, ERp61, GRP57, GRP58, HEL-S-269, HEL-S-93n

NCBI Gene: 2923 ENSG00000167004 UniProt: P30101 OMIM: 602046

This gene encodes a protein of the endoplasmic reticulum that interacts with lectin chaperones calreticulin and calnexin to modulate folding of newly synthesized glycoproteins. The protein was once thought to be a phospholipase; however, it has been demonstrated that the protein actually has protein disulfide isomerase activity. It is thought that complexes of lectins and this protein mediate protein folding by promoting formation of disulfide bonds in their glycoprotein substrates. This protein also functions as a molecular chaperone that prevents the formation of protein aggregates. [provided by RefSeq, Dec 2016]

OMIM Research

OMIM 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

0.25

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.25LOEUF

pLI 0.996

Z-score 4.28

OE 0.08 (0.03–0.25)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.68Z-score

OE missense 0.88 (0.80–0.98)

245 obs / 277.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.25)

0≤0.351.4

Missense OE?0.88 (0.80–0.98)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 2 / 25.2Missense obs/exp: 245 / 277.0Syn Z: 0.26

Background carrier burden — how many people carry a rare variant somewhere in PDIA3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

580 rare PASS variants

Rare truncating (LoF)

1 in 5,000

48 rare PASS variants

Rare synonymous (reference)

1 in 270

217 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PDIA3. 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 140	1 in 6,400
South Asian	~43k	1 in 100	1 in 4,200
Remaining (unassigned)	~30k	1 in 93	≈ 1 in 10,000
European (Finnish)	~27k	1 in 290	1 in 3,800
Admixed American	~22k	1 in 77	≈ 1 in 5,500
African / African American	~21k	1 in 85	≈ 1 in 4,400
East Asian	~20k	1 in 95	1 in 1,500
Ashkenazi Jewish	~13k	1 in 240	≈ 1 in 6,400
Middle Eastern	~2,884	1 in 120	none seen

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): 10 of 13 coding exons well covered in gnomAD exomes; exons 3, 4, 6 marginal. Genomes: all 13.? see exons ↓