Is CASR p.Arg716= (c.2148C>T) pathogenic?

CASR p.Arg716= (c.2148C>T) is classified Likely benign in CASR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-11). Very rare (popmax 8.47e-05%, nfe); Associated with familial hypocalciuric hypercalcemia.

What condition is associated with CASR p.Arg716= (c.2148C>T)?

CASR p.Arg716= (c.2148C>T) is associated with familial hypocalciuric hypercalcemia, autosomal dominant hypocalcemia 1 (ClinVar).

How common is CASR p.Arg716= (c.2148C>T) in the general population?

CASR p.Arg716= (c.2148C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Familial hypocalciuric hypercalcemia inherited?

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

CASR p.Arg716=

c.2148C>T · rs2107650027 · VCV1489985

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

familial hypocalciuric hypercalcemia

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 0.027	GERP 0.16, phastCons 0.75
Overall
CADD	6.721	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,968 alleles

Overall 6.84e-05% 1/1,461,792 alleles · very rare

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: CASR
Protein: p.Arg716=
Coding: c.2148C>T
MANE Select: NM_000388
dbSNP: rs2107650027
Type: single nucleotide variant
Location: chr3:122284102 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 716: a UniProt-annotated variant site (in hhc1; impaired homodimerization; impaired cell membrane localization); the 'intracellular loop 2 (icl2)' region; an α-helix

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

Disease context

familial hypocalciuric hypercalcemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant hypocalcemia 1

For Familial hypocalciuric hypercalcemia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CASR p.Arg716Gly Uncertain significance ★★ ⚠ same residue
CASR p.Arg716Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CASR p.Arg716His Conflicting classifications of pathogenicity ★ ⚠ same residue
CASR p.Arg716Pro Uncertain significance ★ ⚠ same residue
CASR c.1378-1G>C Likely pathogenic ★★ same condition
CASR c.1608+1G>A Likely pathogenic ★★ same condition
CASR c.1609-2A>G Likely pathogenic ★★ same condition
CASR c.186-1G>T Pathogenic ★★ 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/casr-p-arg716 (accessed [today's date]).

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