Is CASR p.Arg752Ser (c.2254C>A) pathogenic?

CASR p.Arg752Ser (c.2254C>A) is classified Uncertain significance in CASR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: ambiguous (0.4851); Absent from gnomAD v4.1; Associated with familial hypocalciuric hypercalcemia.

What condition is associated with CASR p.Arg752Ser (c.2254C>A)?

CASR p.Arg752Ser (c.2254C>A) is associated with familial hypocalciuric hypercalcemia, autosomal dominant hypocalcemia 1 (ClinVar).

How common is CASR p.Arg752Ser (c.2254C>A) in the general population?

CASR p.Arg752Ser (c.2254C>A) is absent from gnomAD v4.1 (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.Arg752Ser (c.2254C>A)?

AlphaMissense predicts ambiguous (score 0.4851) — an in-silico prediction, not a clinical call.

CASR p.Arg752Ser

c.2254C>A · rs193922434 · VCV532583

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4851 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

familial hypocalciuric hypercalcemia

Computational evidence

Protein change
AlphaMissense	0.4851	ambiguous
REVEL	0.656	pathogenic-leaning
SaProt	LLR -7.01	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 660 bp · p 1.4e-08 · regional, not allelic
Overall
CADD	25.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CASR
Protein: p.Arg752Ser
Coding: c.2254C>A
MANE Select: NM_000388
dbSNP: rs193922434
Type: single nucleotide variant
Location: chr3:122284208 (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.Arg752Pro 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-arg752ser (accessed [today's date]).

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