Is CASR p.Cys482Phe (c.1445G>T) pathogenic?

CASR p.Cys482Phe (c.1445G>T) is classified Uncertain significance in CASR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-19). AlphaMissense: likely benign (0.061); Very rare (popmax 8.47e-05%, nfe); Associated with autosomal dominant hypocalcemia 1.

What condition is associated with CASR p.Cys482Phe (c.1445G>T)?

CASR p.Cys482Phe (c.1445G>T) is associated with autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia (ClinVar).

How common is CASR p.Cys482Phe (c.1445G>T) in the general population?

CASR p.Cys482Phe (c.1445G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CASR p.Cys482Phe (c.1445G>T)?

AlphaMissense predicts likely benign (score 0.061) — an in-silico prediction, not a clinical call.

CASR p.Cys482Phe

c.1445G>T · rs761468327 · VCV2922797

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.061 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant hypocalcemia 1

Computational evidence

Protein change
AlphaMissense	0.061	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -2.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 20 kb · p 1.6e-05 · regional, not allelic
Overall
CADD	18.38	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,008 alleles

Overall 0.000657% 1/152,232 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.Cys482Phe
Coding: c.1445G>T
MANE Select: NM_000388
dbSNP: rs761468327
Type: single nucleotide variant
Location: chr3:122275879 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 482: a β-strand; a functional site (important for ability of agonist amg 416 to activate g protein-coupled receptor activity); a disulfide bond

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.Cys482Arg Uncertain significance ★★ ⚠ same residue
CASR p.Cys482Ser Uncertain significance ★ ⚠ same residue
CASR p.Cys482Tyr Likely benign ★ same residue
CASR p.Cys482Gly Uncertain significance ★ ⚠ same residue
CASR p.Cys482= 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

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-cys482phe (accessed [today's date]).

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