Is CASR p.Arg286His (c.857G>A) pathogenic?

CASR p.Arg286His (c.857G>A) is classified Conflicting classifications of pathogenicity in CASR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-08). AlphaMissense: likely benign (0.1248); Very rare (popmax 0.00267%, afr); Associated with familial hypocalciuric hypercalcemia.

What condition is associated with CASR p.Arg286His (c.857G>A)?

CASR p.Arg286His (c.857G>A) is associated with familial hypocalciuric hypercalcemia, familial hypocalciuric hypercalcemia 1, neonatal severe primary hyperparathyroidism (ClinVar).

How common is CASR p.Arg286His (c.857G>A) in the general population?

CASR p.Arg286His (c.857G>A) is very rare (popmax 0.00267%, 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.Arg286His (c.857G>A)?

AlphaMissense predicts likely benign (score 0.1248) — an in-silico prediction, not a clinical call.

CASR p.Arg286His

c.857G>A · rs922511747 · VCV575594

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1248 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial hypocalciuric hypercalcemia

Computational evidence

Protein change
AlphaMissense	0.1248	likely benign
REVEL	0.533	indeterminate
SaProt	LLR -8.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 20 kb · p 1.6e-05 · regional, not allelic
Overall
CADD	22.6	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 0.00267% African / African-American · 2/74,936 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000496% 8/1,614,080 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,468
South Asian	0.0022%	45,541
European (non-Finnish)	0.000339%	295,011

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.Arg286His
Coding: c.857G>A
MANE Select: NM_000388
dbSNP: rs922511747
Type: single nucleotide variant
Location: chr3:122261892 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 286: the 'ligand-binding 2 (lb2)' region; a disulfide bond

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

Disease context

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

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

For Familial hypocalciuric hypercalcemia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CASR p.Arg286Cys Uncertain significance ★★ ⚠ same residue
CASR p.Arg286Pro Uncertain significance ★ ⚠ same residue
CASR p.Arg286Ser Uncertain significance ★ ⚠ same residue
CASR p.Arg286= 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
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-arg286his (accessed [today's date]).

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