CRELD2

Chr 22

CRELD disulfide isomerase 2

NCBI Gene: 79174 ENSG00000184164 UniProt: Q6UXH1 OMIM: 607171

The protein functions as a protein disulfide isomerase in the endoplasmic reticulum and Golgi apparatus, with calcium-binding activity and potential roles in the unfolded protein response and neuronal acetylcholine receptor transport. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, affecting neurological development in infancy. The gene shows tolerance to loss-of-function variation in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable calcium ion binding activity and protein disulfide isomerase activity. Predicted to be located in Golgi apparatus and endoplasmic reticulum. Predicted to be active in extracellular matrix and obsolete extracellular space. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.05

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.05LOEUF

pLI 0.000

Z-score 1.38

OE 0.68 (0.46–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.42Z-score

OE missense 0.92 (0.83–1.03)

221 obs / 239.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.46–1.05)

0≤0.351.4

Missense OE?0.92 (0.83–1.03)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 15 / 22.0Missense obs/exp: 221 / 239.2Syn Z: -0.13

Background carrier burden — how many people carry a rare variant somewhere in CRELD2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 77

574 rare PASS variants

Rare truncating (LoF)

1 in 1,300

107 rare PASS variants

Rare synonymous (reference)

1 in 81

259 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CRELD2. 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 130	1 in 1,700
South Asian	~43k	1 in 79	1 in 520
Remaining (unassigned)	~30k	1 in 63	1 in 610
European (Finnish)	~27k	1 in 270	≈ 1 in 13,000
Admixed American	~22k	1 in 75	1 in 1,100
African / African American	~21k	1 in 59	1 in 410
East Asian	~20k	1 in 58	1 in 2,200
Ashkenazi Jewish	~13k	1 in 570	none seen
Middle Eastern	~2,884	1 in 68	1 in 420

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): 9 of 10 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: 9 of 10 (exon 6 below).? see exons ↓