Is CASR p.Pro559Thr (c.1675C>A) pathogenic?

CASR p.Pro559Thr (c.1675C>A) is classified Conflicting classifications of pathogenicity in CASR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-24). AlphaMissense: likely pathogenic (0.8592); Absent from gnomAD v4.1; Associated with familial hypocalciuric hypercalcemia 1.

What condition is associated with CASR p.Pro559Thr (c.1675C>A)?

CASR p.Pro559Thr (c.1675C>A) is associated with familial hypocalciuric hypercalcemia 1, autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia (ClinVar).

How common is CASR p.Pro559Thr (c.1675C>A) in the general population?

CASR p.Pro559Thr (c.1675C>A) is absent from gnomAD v4.1 (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.Pro559Thr (c.1675C>A)?

AlphaMissense predicts likely pathogenic (score 0.8592) — an in-silico prediction, not a clinical call.

CASR p.Pro559Thr

c.1675C>A · VCV3755630

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8592 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypocalciuric hypercalcemia 1

Computational evidence

Protein change
AlphaMissense	0.8592	likely pathogenic
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 20 kb · p 1.6e-05 · regional, not allelic
Overall
CADD	24.6	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

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.Pro559Thr
Coding: c.1675C>A
MANE Select: NM_000388
Type: single nucleotide variant
Location: chr3:122282179 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 559: the 'cysteine-rich (cr)' region; a disulfide bond

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: autosomal dominant hypocalcemia 1 familial hypocalciuric hypercalcemia

For Familial hypocalciuric hypercalcemia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CASR p.Pro559= Likely benign ★★ same residue
CASR p.Pro559His 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

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-pro559thr (accessed [today's date]).

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