Is CASR p.Arg69Ser (c.205C>A) pathogenic?

CASR p.Arg69Ser (c.205C>A) is classified Likely pathogenic in CASR (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-29). AlphaMissense: likely pathogenic (0.9898); Absent from gnomAD v4.1; Associated with neonatal severe primary hyperparathyroidism.

What condition is associated with CASR p.Arg69Ser (c.205C>A)?

CASR p.Arg69Ser (c.205C>A) is associated with neonatal severe primary hyperparathyroidism (ClinVar).

How common is CASR p.Arg69Ser (c.205C>A) in the general population?

CASR p.Arg69Ser (c.205C>A) 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.Arg69Ser (c.205C>A)?

AlphaMissense predicts likely pathogenic (score 0.9898) — an in-silico prediction, not a clinical call.

CASR p.Arg69Ser

c.205C>A · rs1313627454 · VCV1803180

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9898 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neonatal severe primary hyperparathyroidism

Computational evidence

Protein change
AlphaMissense	0.9898	likely pathogenic ✓ concordant with ClinVar · top 7% in CASR
REVEL	0.744	pathogenic-leaning
SaProt	LLR -11.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.26	acceptor loss, 19 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 7,518 bp · p 3.2e-17 · regional, not allelic
Overall
CADD	26.9	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

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.Arg69Ser
Coding: c.205C>A
MANE Select: NM_000388
dbSNP: rs1313627454
Type: single nucleotide variant
Location: chr3:122257100 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 69: the 'ligand-binding 1 (lb1)' region; an α-helix; a binding site; a disulfide bond

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

For Neonatal severe primary hyperparathyroidism (Orphanet):

Inheritance: Autosomal recessive, Not applicable
Onset: Neonatal

Similar variants

CASR p.Arg69His Pathogenic/Likely pathogenic ★★ same residue
CASR p.Arg69Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CASR p.Arg69Gly Uncertain significance ★ ⚠ same residue
CASR p.Arg69= Likely benign ★ same residue
CASR c.493-2A>C Likely pathogenic ★★ same condition
CASR p.Arg185Gln Pathogenic ★★ same condition
CASR p.Arg185Ter Pathogenic ★★ same condition
CASR p.Arg220Trp 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-arg69ser (accessed [today's date]).

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