Is CASR p.Arg886Pro (c.2657G>C) pathogenic?

CASR p.Arg886Pro (c.2657G>C) is classified Pathogenic in CASR (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.9151); Very rare (popmax 8.47e-05%, nfe); Associated with CASR-related disorder.

What condition is associated with CASR p.Arg886Pro (c.2657G>C)?

CASR p.Arg886Pro (c.2657G>C) is associated with CASR-related disorder, familial hypocalciuric hypercalcemia 1, autosomal dominant hypocalcemia 1 (ClinVar).

How common is CASR p.Arg886Pro (c.2657G>C) in the general population?

CASR p.Arg886Pro (c.2657G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CASR p.Arg886Pro (c.2657G>C)?

AlphaMissense predicts likely pathogenic (score 0.9151) — an in-silico prediction, not a clinical call.

CASR p.Arg886Pro

c.2657G>C · rs1057520791 · VCV379932

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9151 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CASR-related disorder

Computational evidence

Protein change
AlphaMissense	0.9151	likely pathogenic ✓ concordant with ClinVar
REVEL	0.75	pathogenic-leaning
SaProt	LLR -7.55	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 153 bp · p 0.00027 · regional, not allelic
Overall
CADD	25.8	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 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.84e-05% 1/1,461,762 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.Arg886Pro
Coding: c.2657G>C
MANE Select: NM_000388
dbSNP: rs1057520791
Type: single nucleotide variant
Location: chr3:122284611 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 886: a UniProt-annotated variant site (in hhc1; impaired homodimerization; impaired cell membrane localization); a UniProt-annotated variant site (in hhc1; increased localization to the plasma membrane); a UniProt-annotated variant site (in hhc1); the 'c-terminus' region; the 'interaction with rnf19a' 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 autosomal dominant hypocalcemia 1 familial hypocalciuric hypercalcemia

Similar variants

CASR p.Arg886Trp Pathogenic ★★ ⚠ same residue
CASR p.Arg886Gln Uncertain significance ★★ ⚠ same residue
CASR p.Arg886Gly Uncertain significance ★★ ⚠ same residue
CASR p.Arg886= Likely benign ★★ 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

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-arg886pro (accessed [today's date]).

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