Is CASR p.Pro221= (c.663G>A) pathogenic?

CASR p.Pro221= (c.663G>A) is classified Likely benign in CASR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-05). Very rare (popmax 0.00534%, afr); Associated with autosomal dominant hypocalcemia 1.

What condition is associated with CASR p.Pro221= (c.663G>A)?

CASR p.Pro221= (c.663G>A) is associated with autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia (ClinVar).

How common is CASR p.Pro221= (c.663G>A) in the general population?

CASR p.Pro221= (c.663G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

CASR p.Pro221=

c.663G>A · rs750830429 · VCV1055353

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

autosomal dominant hypocalcemia 1

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 -0.33	GERP -3.4
Overall
CADD	5.186	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,932 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000558% 9/1,614,066 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,733
East Asian	0.00223%	44,894
South Asian	0.0022%	45,541
European (non-Finnish)	0.000169%	590,009

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.Pro221=
Coding: c.663G>A
MANE Select: NM_000388
dbSNP: rs750830429
Type: single nucleotide variant
Location: chr3:122261698 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 221: a UniProt-annotated variant site (in hypoc1; increased g protein-coupled receptor signaling); a UniProt-annotated variant site (in hhc1); a UniProt-annotated variant site (in hhc1; decreased g protein-coupled receptor signaling pathway); the 'ligand-binding 2 (lb2)' region; an α-helix

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

Disease context

autosomal dominant hypocalcemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypocalciuric hypercalcemia

Similar variants

CASR p.Pro221Leu Pathogenic ★★ ⚠ same residue
CASR p.Pro221Gln Uncertain significance ★ ⚠ same residue
CASR p.Pro221Ser Pathogenic ★ ⚠ 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
CASR c.493-2A>C 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-pro221 (accessed [today's date]).

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