Is CASR p.Pro22Ser (c.64C>T) pathogenic?

CASR p.Pro22Ser (c.64C>T) is classified Uncertain significance in CASR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-03). AlphaMissense: ambiguous (0.3745); Absent from gnomAD v4.1; Associated with CASR-related disorder.

What condition is associated with CASR p.Pro22Ser (c.64C>T)?

CASR p.Pro22Ser (c.64C>T) is associated with CASR-related disorder (ClinVar).

How common is CASR p.Pro22Ser (c.64C>T) in the general population?

CASR p.Pro22Ser (c.64C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASR p.Pro22Ser (c.64C>T)?

AlphaMissense predicts ambiguous (score 0.3745) — an in-silico prediction, not a clinical call.

CASR p.Pro22Ser

c.64C>T · rs2473205246 · VCV2633924

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3745 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

CASR-related disorder

Computational evidence

Protein change
AlphaMissense	0.3745	ambiguous
REVEL	0.525	indeterminate
SaProt	LLR -5.80	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	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	22.0	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.Pro22Ser
Coding: c.64C>T
MANE Select: NM_000388
dbSNP: rs2473205246
Type: single nucleotide variant
Location: chr3:122254253 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 22: the 'ligand-binding 1 (lb1)' region; a β-strand

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

Disease context

CASR-related disorder

Similar variants

CASR p.Pro22= Likely benign ★★ same residue
CASR p.Pro22Thr Uncertain significance ★ ⚠ same residue
CASR p.Arg220Trp Pathogenic/Likely pathogenic ★★ same condition
CASR p.Arg227Ter Pathogenic/Likely pathogenic ★★ same condition
CASR p.Arg392Ter Pathogenic ★★ same condition
CASR p.Arg544Ter Pathogenic ★★ same condition
CASR p.Arg680His Pathogenic/Likely pathogenic ★★ same condition
CASR p.Arg886Pro 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-pro22ser (accessed [today's date]).

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