Is CASR p.Arg331Pro (c.992G>C) pathogenic?

CASR p.Arg331Pro (c.992G>C) is classified Uncertain significance in CASR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: likely benign (0.2206); Absent from gnomAD v4.1; Associated with familial hypocalciuric hypercalcemia.

What condition is associated with CASR p.Arg331Pro (c.992G>C)?

CASR p.Arg331Pro (c.992G>C) is associated with familial hypocalciuric hypercalcemia, autosomal dominant hypocalcemia 1 (ClinVar).

How common is CASR p.Arg331Pro (c.992G>C) in the general population?

CASR p.Arg331Pro (c.992G>C) 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.Arg331Pro (c.992G>C)?

AlphaMissense predicts likely benign (score 0.2206) — an in-silico prediction, not a clinical call.

CASR p.Arg331Pro

c.992G>C · rs747090029 · VCV1421675

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2206 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypocalciuric hypercalcemia

Computational evidence

Protein change
AlphaMissense	0.2206	likely benign
REVEL	0.744	pathogenic-leaning
SaProt	LLR -8.01	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.2, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 20 kb · p 1.6e-05 · regional, not allelic
Overall
CADD	24.8	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.Arg331Pro
Coding: c.992G>C
MANE Select: NM_000388
dbSNP: rs747090029
Type: single nucleotide variant
Location: chr3:122262027 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 331: 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.Arg331Gln Uncertain significance ★★ ⚠ same residue
CASR p.Arg331Leu Uncertain significance ★★ ⚠ same residue
CASR p.Arg331Trp Uncertain significance ★★ ⚠ same residue
CASR p.Arg331= Likely benign ★ 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-arg331pro (accessed [today's date]).

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