Is CASR p.Arg752Pro (c.2255G>C) pathogenic?

CASR p.Arg752Pro (c.2255G>C) is classified Uncertain significance in CASR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-22). AlphaMissense: likely pathogenic (0.7395); Very rare (popmax 0.000254%, nfe); Associated with familial hypocalciuric hypercalcemia.

What condition is associated with CASR p.Arg752Pro (c.2255G>C)?

CASR p.Arg752Pro (c.2255G>C) is associated with familial hypocalciuric hypercalcemia, autosomal dominant hypocalcemia 1 (ClinVar).

How common is CASR p.Arg752Pro (c.2255G>C) in the general population?

CASR p.Arg752Pro (c.2255G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Familial hypocalciuric hypercalcemia inherited?

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

What do computational predictors say about CASR p.Arg752Pro (c.2255G>C)?

AlphaMissense predicts likely pathogenic (score 0.7395) — an in-silico prediction, not a clinical call.

CASR p.Arg752Pro

c.2255G>C · rs771529256 · VCV1423260

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7395 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypocalciuric hypercalcemia

Computational evidence

Protein change
AlphaMissense	0.7395	likely pathogenic
REVEL	0.725	pathogenic-leaning
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 660 bp · p 1.4e-08 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,014 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,684 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.Arg752Pro
Coding: c.2255G>C
MANE Select: NM_000388
dbSNP: rs771529256
Type: single nucleotide variant
Location: chr3:122284209 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 752: a UniProt-annotated variant site (in hhc1; impaired homodimerization; impaired cell membrane localization); a β-strand

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.Arg752Gly Uncertain significance ★★ ⚠ same residue
CASR p.Arg752Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CASR p.Arg752His Conflicting classifications of pathogenicity ★ ⚠ same residue
CASR p.Arg752Ser Uncertain significance ★ ⚠ same residue
CASR p.Arg752fs Pathogenic ★ same residue
CASR p.Arg752= Likely benign ★ same residue
CASR c.1378-1G>C Likely pathogenic ★★ same condition
CASR c.1608+1G>A Likely 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-arg752pro (accessed [today's date]).

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