Is CASR p.Arg866Cys (c.2596C>T) pathogenic?

CASR p.Arg866Cys (c.2596C>T) is classified Uncertain significance in CASR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-01). AlphaMissense: likely benign (0.3096); Absent from gnomAD v4.1; Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with CASR p.Arg866Cys (c.2596C>T)?

CASR p.Arg866Cys (c.2596C>T) is associated with Nephrolithiasis/nephrocalcinosis, autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia (ClinVar).

How common is CASR p.Arg866Cys (c.2596C>T) in the general population?

CASR p.Arg866Cys (c.2596C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASR p.Arg866Cys (c.2596C>T)?

AlphaMissense predicts likely benign (score 0.3096) — an in-silico prediction, not a clinical call.

CASR p.Arg866Cys

c.2596C>T · rs1576878170 · VCV660501

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3096 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,026)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.3096	likely benign
REVEL	0.675	pathogenic-leaning
SaProt	LLR -10.05	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.1, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 153 bp · p 0.00027 · regional, not allelic
Overall
CADD	24.5	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

No allele count reported in gnomAD v4.1 (AN 1,614,026). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CASR
Protein: p.Arg866Cys
Coding: c.2596C>T
MANE Select: NM_000388
dbSNP: rs1576878170
Type: single nucleotide variant
Location: chr3:122284550 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 866: a UniProt-annotated variant site (in hhc1; impaired homodimerization; impaired cell membrane localization); the 'c-terminus' region; a β-strand

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

Disease context

Nephrolithiasis/nephrocalcinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant hypocalcemia 1 familial hypocalciuric hypercalcemia

Similar variants

CASR p.Arg866His Uncertain significance ★★ ⚠ same residue
CASR p.Arg866Pro Uncertain significance ★★ ⚠ same residue
CASR p.Arg866Gly Uncertain significance ★ ⚠ same residue
CASR p.Arg866= Likely benign ★ same residue
CASR p.Arg866Leu 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

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-arg866cys (accessed [today's date]).

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