Is CASR p.Ala645Asp (c.1934C>A) pathogenic?

CASR p.Ala645Asp (c.1934C>A) is classified Likely pathogenic in CASR (ClinVar, Single submitter, 1 submitter; last evaluated 2011-08-18). AlphaMissense: likely pathogenic (0.9808); Absent from gnomAD v4.1; Associated with familial hypoparathyroidism.

What condition is associated with CASR p.Ala645Asp (c.1934C>A)?

CASR p.Ala645Asp (c.1934C>A) is associated with familial hypoparathyroidism (ClinVar).

How common is CASR p.Ala645Asp (c.1934C>A) in the general population?

CASR p.Ala645Asp (c.1934C>A) is absent from gnomAD v4.1 (gnomAD).

How is Familial isolated hypoparathyroidism inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CASR p.Ala645Asp (c.1934C>A)?

AlphaMissense predicts likely pathogenic (score 0.9808) — an in-silico prediction, not a clinical call.

CASR p.Ala645Asp

c.1934C>A · rs193922430 · VCV35785

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9808 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypoparathyroidism

Computational evidence

Protein change
AlphaMissense	0.9808	likely pathogenic ✓ concordant with ClinVar · top 10% in CASR
REVEL	0.944	strongly pathogenic-leaning
SaProt	LLR -12.44	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 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 660 bp · p 1.4e-08 · regional, not allelic
Overall
CADD	29.2	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.Ala645Asp
Coding: c.1934C>A
MANE Select: NM_000388
dbSNP: rs193922430
Type: single nucleotide variant
Location: chr3:122283888 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 645: a UniProt-annotated variant site (in hhc1; impaired homodimerization; impaired cell membrane localization); the 'intracellular loop 1 (icl1)' region; an α-helix

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

Disease context

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

For Familial isolated hypoparathyroidism (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: All ages

Similar variants

CASR p.Ala645= Likely benign ★★ same residue
CASR p.Ala645Thr Uncertain significance ★ ⚠ same residue
CASR p.Pro221Leu Pathogenic ★★ ⚠ same condition
CASR p.Thr151Met Pathogenic ★★ ⚠ same condition
CASR p.Ala850Gly Uncertain significance ★★ ⚠ same condition
CASR p.Asp217Asn Uncertain significance ★★ ⚠ same condition
CASR c.*1015A>G Benign ★★ same condition
CASR c.*1093C>T Benign ★★ 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-ala645asp (accessed [today's date]).

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