Is CASR p.Pro163Arg (c.488C>G) pathogenic?

CASR p.Pro163Arg (c.488C>G) is classified Conflicting classifications of pathogenicity in CASR (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-03-13). AlphaMissense: likely pathogenic (0.999); Very rare (popmax 8.48e-05%, nfe); Associated with CASR-related disorder.

What condition is associated with CASR p.Pro163Arg (c.488C>G)?

CASR p.Pro163Arg (c.488C>G) is associated with CASR-related disorder, familial hypocalciuric hypercalcemia 1 (ClinVar).

How common is CASR p.Pro163Arg (c.488C>G) in the general population?

CASR p.Pro163Arg (c.488C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CASR p.Pro163Arg (c.488C>G)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

CASR p.Pro163Arg

c.488C>G · rs2107627915 · VCV2684152

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CASR-related disorder

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic · top 2% in CASR
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -16.49	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 1.9, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 7,518 bp · p 3.2e-17 · regional, not allelic
Overall
CADD	29.4	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,390 alleles

Overall 6.85e-05% 1/1,460,794 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CASR
Protein: p.Pro163Arg
Coding: c.488C>G
MANE Select: NM_000388
dbSNP: rs2107627915
Type: single nucleotide variant
Location: chr3:122257383 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 163: the 'ligand-binding 1 (lb1)' region

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

Disease context

CASR-related disorder

Also linked: familial hypocalciuric hypercalcemia 1

Similar variants

CASR p.Pro163Leu Uncertain significance ★ ⚠ same residue
CASR p.Pro163Ser Uncertain significance ★ ⚠ same residue
CASR p.Pro163= Likely benign ★ same residue
CASR c.1609-2A>G Likely pathogenic ★★ same condition
CASR c.186-1G>T Pathogenic ★★ same condition
CASR p.Ala581Val Likely pathogenic ★★ ⚠ same condition
CASR p.Arg185Gln Pathogenic ★★ same condition
CASR p.Arg185Ter 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-pro163arg (accessed [today's date]).

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