Is ORAI1 p.Pro44= (c.132A>G) pathogenic?

ORAI1 p.Pro44= (c.132A>G) is classified Benign/Likely benign in ORAI1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-01). Rare (popmax 0.642%, nfe); Associated with combined immunodeficiency due to ORAI1 deficiency.

How common is ORAI1 p.Pro44= (c.132A>G) in the general population?

ORAI1 p.Pro44= (c.132A>G) is rare (popmax 0.642%, nfe) (gnomAD).

ORAI1 p.Pro44=

Q: What condition is associated with ORAI1 p.Pro44= (c.132A>G)?

ORAI1 p.Pro44= (c.132A>G) is associated with combined immunodeficiency due to ORAI1 deficiency, myopathy, tubular aggregate, 2 (ClinVar).

Q: How is Combined immunodeficiency due to CRAC channel dysfunction inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.132A>G · rs554617167 · VCV779605

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.642%, nfe)

Conditions

combined immunodeficiency due to ORAI1 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.61	GERP -2.2, phastCons 0.11
Overall
CADD	5.422	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.642% European (non-Finnish) · 7,393/1,150,690 alleles

Filtering AF 0.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.625%

Overall 0.549% 8,518/1,550,962 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.674%	148
European (non-Finnish)grpmax	0.642%	156
Remaining individualsnot grpmax-eligible	0.395%	253
South Asian	0.379%	264
Middle Eastern	0.146%	684
Admixed American	0.138%	722
African / African-American	0.0997%	1,003
Ashkenazi Jewishnot grpmax-eligible	0.0613%	1,631
East Asian	0.00512%	19,523

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ORAI1
Protein: p.Pro44=
Coding: c.132A>G
dbSNP: rs554617167
Type: single nucleotide variant
Location: chr12:121626879 (GRCh38)
Gene constraint: LOEUF 1.24 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.84 · 2 PDB
Residue 44: the 'disordered' region; the 'required for generation of inwardly rectifying crac currents' region; the 'akap5 association region' region

Full ORAI1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined immunodeficiency due to ORAI1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myopathy, tubular aggregate, 2

For Combined immunodeficiency due to CRAC channel dysfunction (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ORAI1 p.Pro44Leu Uncertain significance ★ ⚠ same residue
ORAI1 p.Arg268Ter Likely pathogenic ★★ same condition
ORAI1 p.Leu194Pro Likely pathogenic ★★ same condition
ORAI1 p.Ala111Thr Uncertain significance ★★ ⚠ same condition
ORAI1 p.Ala132Gly Uncertain significance ★★ ⚠ same condition
ORAI1 p.Ala217Thr Uncertain significance ★★ ⚠ same condition
ORAI1 p.Asn158Ser Uncertain significance ★★ ⚠ same condition
ORAI1 p.Gly20Cys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/orai1-p-pro44 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown