Is CASR p.Pro221Ser (c.661C>T) pathogenic?

CASR p.Pro221Ser (c.661C>T) is classified Pathogenic in CASR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-01). AlphaMissense: likely pathogenic (0.7985); Absent from gnomAD v4.1; Associated with autosomal dominant hypocalcemia.

What condition is associated with CASR p.Pro221Ser (c.661C>T)?

CASR p.Pro221Ser (c.661C>T) is associated with autosomal dominant hypocalcemia (ClinVar).

How common is CASR p.Pro221Ser (c.661C>T) in the general population?

CASR p.Pro221Ser (c.661C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASR p.Pro221Ser (c.661C>T)?

AlphaMissense predicts likely pathogenic (score 0.7985) — an in-silico prediction, not a clinical call.

CASR p.Pro221Ser

c.661C>T · rs2473225928 · VCV3068868

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7985 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant hypocalcemia

Computational evidence

Protein change
AlphaMissense	0.7985	likely pathogenic ✓ concordant with ClinVar
REVEL	0.651	pathogenic-leaning
SaProt	LLR -5.18	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 6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 7,518 bp · p 3.2e-17 · regional, not allelic
Overall
CADD	19.83	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.Pro221Ser
Coding: c.661C>T
MANE Select: NM_000388
dbSNP: rs2473225928
Type: single nucleotide variant
Location: chr3:122261696 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASR p.Pro221Leu Pathogenic ★★ ⚠ same residue
CASR p.Pro221= Likely benign ★★ same residue
CASR p.Pro221Gln Uncertain significance ★ ⚠ same residue
CASR p.Glu604Lys Pathogenic ★★ same condition
CASR p.Glu767Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
CASR p.Gly670Arg Pathogenic/Likely pathogenic ★★ same condition
CASR p.Met811Val Likely pathogenic ★★ same condition
CASR p.Thr151Met 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-pro221ser (accessed [today's date]).

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