Is CASR p.Arg680Cys (c.2038C>T) pathogenic?

CASR p.Arg680Cys (c.2038C>T) is classified Pathogenic in CASR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.7945); Very rare (popmax 0.00133%, afr); Associated with familial hypocalciuric hypercalcemia 1.

What condition is associated with CASR p.Arg680Cys (c.2038C>T)?

CASR p.Arg680Cys (c.2038C>T) is associated with familial hypocalciuric hypercalcemia 1, neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1 (ClinVar).

How common is CASR p.Arg680Cys (c.2038C>T) in the general population?

CASR p.Arg680Cys (c.2038C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Familial hypocalciuric hypercalcemia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CASR p.Arg680Cys (c.2038C>T)?

AlphaMissense predicts likely pathogenic (score 0.7945) — an in-silico prediction, not a clinical call.

CASR p.Arg680Cys

c.2038C>T · rs767363250 · VCV410347

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7945 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypocalciuric hypercalcemia 1

Computational evidence

Protein change
AlphaMissense	0.7945	likely pathogenic ✓ concordant with ClinVar
REVEL	0.853	moderately pathogenic-leaning
SaProt	LLR -12.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 660 bp · p 1.4e-08 · regional, not allelic
Overall
CADD	33.0	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 0.00133% African / African-American · 1/74,910 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000682% 11/1,613,656 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,238
African / African-Americangrpmax	0.00133%	74,910
European (non-Finnish)	0.000678%	147,482

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg680Cys
Coding: c.2038C>T
MANE Select: NM_000388
dbSNP: rs767363250
Type: single nucleotide variant
Location: chr3:122283992 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 680: a UniProt-annotated variant site (in hhc1; impaired homodimerization; impaired cell membrane localization); a UniProt-annotated variant site (in hhc1)

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

Disease context

familial hypocalciuric hypercalcemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neonatal severe primary hyperparathyroidism autosomal dominant hypocalcemia 1 epilepsy, idiopathic generalized, susceptibility to, 8 familial hypocalciuric hypercalcemia

For Familial hypocalciuric hypercalcemia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CASR p.Arg680His Pathogenic/Likely 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
CASR p.Ala581Val Likely pathogenic ★★ ⚠ same condition
CASR p.Ala835Asp Pathogenic/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-arg680cys (accessed [today's date]).

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