Is CASR p.Lys29Arg (c.86A>G) pathogenic?

CASR p.Lys29Arg (c.86A>G) is classified Uncertain significance in CASR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.0954); Absent from gnomAD v4.1; Associated with neonatal severe primary hyperparathyroidism.

What condition is associated with CASR p.Lys29Arg (c.86A>G)?

CASR p.Lys29Arg (c.86A>G) is associated with neonatal severe primary hyperparathyroidism, familial hypocalciuric hypercalcemia 1, autosomal dominant hypocalcemia 1 (ClinVar).

How common is CASR p.Lys29Arg (c.86A>G) in the general population?

CASR p.Lys29Arg (c.86A>G) is absent from gnomAD v4.1 (gnomAD).

How is Neonatal severe primary hyperparathyroidism inherited?

Typically Autosomal recessive, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CASR p.Lys29Arg (c.86A>G)?

AlphaMissense predicts likely benign (score 0.0954) — an in-silico prediction, not a clinical call.

CASR p.Lys29Arg

c.86A>G · VCV3588340

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0954 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neonatal severe primary hyperparathyroidism

Computational evidence

Protein change
AlphaMissense	0.0954	likely benign
REVEL	0.471	indeterminate
SaProt	LLR -6.17	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 7,518 bp · p 3.2e-17 · regional, not allelic
Overall
CADD	23.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CASR
Protein: p.Lys29Arg
Coding: c.86A>G
MANE Select: NM_000388
Type: single nucleotide variant
Location: chr3:122254275 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 29: the 'ligand-binding 1 (lb1)' region; a UniProt-annotated variant site (in hypoc1; increased calcium sensitivity)

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

Disease context

neonatal severe primary hyperparathyroidism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Neonatal severe primary hyperparathyroidism (Orphanet):

Inheritance: Autosomal recessive, Not applicable
Onset: Neonatal

Similar variants

CASR p.Lys29= Likely benign ★ same residue
CASR p.Lys29Glu 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

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-lys29arg (accessed [today's date]).

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