Is CASR p.Arg220Gln (c.659G>A) pathogenic?

CASR p.Arg220Gln (c.659G>A) is classified Pathogenic/Likely pathogenic in CASR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-29). AlphaMissense: ambiguous (0.5002); Very rare (popmax 6.84e-05%); Associated with autosomal dominant hypocalcemia 1.

What condition is associated with CASR p.Arg220Gln (c.659G>A)?

CASR p.Arg220Gln (c.659G>A) is associated with autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia 1, familial hypocalciuric hypercalcemia (ClinVar).

How common is CASR p.Arg220Gln (c.659G>A) in the general population?

CASR p.Arg220Gln (c.659G>A) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about CASR p.Arg220Gln (c.659G>A)?

AlphaMissense predicts ambiguous (score 0.5002) — an in-silico prediction, not a clinical call.

CASR p.Arg220Gln

c.659G>A · rs1202110240 · VCV448997

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5002 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

autosomal dominant hypocalcemia 1

Computational evidence

Protein change
AlphaMissense	0.5002	ambiguous
REVEL	0.74	pathogenic-leaning
SaProt	LLR -8.87	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 10	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	23.6	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 6.84e-05%

Overall 6.84e-05% 1/1,461,872 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.Arg220Gln
Coding: c.659G>A
MANE Select: NM_000388
dbSNP: rs1202110240
Type: single nucleotide variant
Location: chr3:122261694 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 220: a UniProt-annotated variant site (in hhc1); 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 1 familial hypocalciuric hypercalcemia

Similar variants

CASR p.Arg220Trp Pathogenic/Likely pathogenic ★★ same residue
CASR p.Arg220= Likely benign ★★ same residue
CASR p.Arg220Pro Pathogenic ★ same residue
CASR p.Arg220Leu Uncertain significance ★ ⚠ 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-arg220gln (accessed [today's date]).

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