Is CASR p.Cys565Phe (c.1694G>T) pathogenic?

CASR p.Cys565Phe (c.1694G>T) is classified Conflicting classifications of pathogenicity in CASR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-30). AlphaMissense: likely pathogenic (0.9984); Absent from gnomAD v4.1; Associated with autosomal dominant hypocalcemia 1.

What condition is associated with CASR p.Cys565Phe (c.1694G>T)?

CASR p.Cys565Phe (c.1694G>T) is associated with autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia (ClinVar).

How common is CASR p.Cys565Phe (c.1694G>T) in the general population?

CASR p.Cys565Phe (c.1694G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASR p.Cys565Phe (c.1694G>T)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

CASR p.Cys565Phe

c.1694G>T · VCV3380979

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant hypocalcemia 1

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic · top 2% in CASR
REVEL	0.879	moderately pathogenic-leaning
SaProt	LLR -14.58	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 1,593 bp · p 1.6e-07 · regional, not allelic
Overall
CADD	32.0	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

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.Cys565Phe
Coding: c.1694G>T
MANE Select: NM_000388
Type: single nucleotide variant
Location: chr3:122282198 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 565: a UniProt-annotated variant site (in hhc1); the 'cysteine-rich (cr)' region; a β-strand; a disulfide bond

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

Disease context

autosomal dominant hypocalcemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypocalciuric hypercalcemia

Similar variants

CASR p.Cys565Gly Uncertain significance ★★ ⚠ same residue
CASR p.Cys565Arg Uncertain significance ★ ⚠ same residue
CASR p.Cys565Tyr Uncertain significance ★ ⚠ 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

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-cys565phe (accessed [today's date]).

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