# NM_000388.4(CASR):c.553C>A (p.Arg185=)

https://sugi.bio/variant/casr-p-arg185

## Summary

**CASR p.Arg185= (c.553C>A)** is classified **Likely benign** in CASR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-07-10). Very rare (popmax 0.00833%, amr); Associated with familial hypocalciuric hypercalcemia.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs104893707 · 3 submitters · 2 linked conditions · very rare (popmax 0.00833%, amr)

## For patients & families {#patients}

This is a change in the CASR gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to familial hypocalciuric hypercalcemia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | All ages |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CASR is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Familial hypocalciuric hypercalcemia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypercalcemia — Obligate (100%)
- Hypocalciuria — Obligate (100%)
- Reduced ratio of renal calcium clearance to creatinine clearance — Very frequent (99-80%)
- Parathormone-independent increased renal tubular calcium reabsorption — Very frequent (99-80%)
- Osteomalacia — Frequent (79-30%)
- Renal hypophosphatemia — Frequent (79-30%)
- Hypercalcemia — Frequent (79-30%)
- Chondrocalcinosis — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010828/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CASR](https://sugi.bio/atlas/gene/CASR/) |
| Protein change (HGVS p.) | p.Arg185= |
| Coding change (HGVS c.) | c.553C>A |
| MANE Select transcript | [NM_000388](https://www.ncbi.nlm.nih.gov/nuccore/NM_000388) |
| dbSNP | [rs104893707](https://www.ncbi.nlm.nih.gov/snp/rs104893707/) |
| Variant type | single nucleotide variant |
| Location | chr3:122261588-122261588 (GRCh38) |
| ClinVar | [VCV532592](https://www.ncbi.nlm.nih.gov/clinvar/variation/532592/) |

**All HGVS expressions:** `NC_000003.11:g.121980435C>A`, `NC_000003.12:g.122261588C>A`, `NG_009058.1:g.82906C>A`, `NM_000388.4:c.553C>A`, `NM_001178065.2:c.553C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 5.999, GERP 2.09, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 12.52**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00833%** (amr) · FAF95 0.00323% · FAF99 0.00207% · 5/60,004 in the highest group · 16/1,614,058 alleles overall — very rare (popmax 0.00833%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00833% | 12,001 |
| European (non-Finnish) | 0.000932% | 107,274 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CASR** population constraint: LOEUF 0.469, pLI 0.99692, missense-Z 4.8379. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **neonatal severe primary hyperparathyroidism** — Definitive (AR)
- **familial hypocalciuric hypercalcemia 1** — Definitive (AD)
- **epilepsy** — Refuted (AD)
- **autosomal dominant hypocalcemia 1** — Definitive (AD)

## Protein context {#protein}

Residue **185** lies in a UniProt-annotated variant site (in hhc1; decreased g protein-coupled receptor signaling pathway); the 'ligand-binding 1 (lb1)' region; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 76.01, 43% of residues very-high.

**31 experimental structure(s)** (PDB): [5FBH](https://www.rcsb.org/structure/5FBH), [5FBK](https://www.rcsb.org/structure/5FBK), [5K5S](https://www.rcsb.org/structure/5K5S), [5K5T](https://www.rcsb.org/structure/5K5T), [7DTT](https://www.rcsb.org/structure/7DTT), [7DTU](https://www.rcsb.org/structure/7DTU).

## What this gene does {#gene-function}

*Describes the biological roles of CASR (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CASR's established molecular role includes G protein-coupled receptor activity. p.Arg185= falls in the ligand-binding 1 (lb1) region.


### Pathways affected {#pathways}

CASR participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Class C/3 (Metabotropic glutamate/pheromone receptors)](https://reactome.org/content/detail/R-HSA-420499) | curated |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | curated |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** G protein-coupled receptor activity, calcium ion binding, amino acid binding, identical protein binding, protein homodimerization activity.

**Biological process:** detection of calcium ion, intracellular calcium ion homeostasis, G protein-coupled receptor signaling pathway, adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway, phospholipase C-activating G protein-coupled receptor signaling pathway, positive regulation of NLRP3 inflammasome complex assembly.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-07-10.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 3 submissions (2019–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-03-31 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-10 |

## Associated conditions {#conditions}

[familial hypocalciuric hypercalcemia](https://sugi.bio/atlas/disease/familial-hypocalciuric-hypercalcemia/), [autosomal dominant hypocalcemia 1](https://sugi.bio/atlas/disease/autosomal-dominant-hypocalcemia-1/).

**Reported phenotype names (ClinVar):** Familial hypocalciuric hypercalcemia, Autosomal dominant hypocalcemia 1, Nephrolithiasis/nephrocalcinosis, Thyroid cancer, nonmedullary, 1, Familial benign hypercalcemia, HYPOCALCEMIA, FAMILIAL.

## Same-residue context {#hotspot}

Residue **185** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [CASR p.Arg185fs](/variant/casr-p-arg185fs), [CASR p.Arg185Gln](/variant/casr-p-arg185gln), [CASR p.Arg185Ter](/variant/casr-p-arg185ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CASR variant pages (same residue, condition, or type): [CASR p.Arg185Gln](/variant/casr-p-arg185gln), [CASR p.Arg185Ter](/variant/casr-p-arg185ter), [CASR p.Arg185Leu](/variant/casr-p-arg185leu), [CASR p.Arg185fs](/variant/casr-p-arg185fs), [CASR p.Arg185Pro](/variant/casr-p-arg185pro), [CASR c.1378-1G>C](/variant/casr-c-1378-minus-1g-c), [CASR c.1608+1G>A](/variant/casr-c-1608-plus-1g-a), [CASR c.1609-2A>G](/variant/casr-c-1609-minus-2a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 532592). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*