Is CASR p.Arg441Lys (c.1322G>A) pathogenic?

CASR p.Arg441Lys (c.1322G>A) is classified Uncertain significance in CASR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-24). AlphaMissense: likely benign (0.0636); Very rare (popmax 0.00223%, eas); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with CASR p.Arg441Lys (c.1322G>A)?

CASR p.Arg441Lys (c.1322G>A) is associated with Nephrolithiasis/nephrocalcinosis, autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia (ClinVar).

How common is CASR p.Arg441Lys (c.1322G>A) in the general population?

CASR p.Arg441Lys (c.1322G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CASR p.Arg441Lys (c.1322G>A)?

AlphaMissense predicts likely benign (score 0.0636) — an in-silico prediction, not a clinical call.

CASR p.Arg441Lys

c.1322G>A · rs1230573005 · VCV1389175

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.0636	likely benign
REVEL	0.202	benign-leaning
SaProt	LLR -3.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.14, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 20 kb · p 1.6e-05 · regional, not allelic
Overall
CADD	11.91	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,902 alleles

Overall 0.000657% 1/152,202 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.Arg441Lys
Coding: c.1322G>A
MANE Select: NM_000388
dbSNP: rs1230573005
Type: single nucleotide variant
Location: chr3:122262357 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 441: a β-strand; a disulfide bond

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

Disease context

Nephrolithiasis/nephrocalcinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant hypocalcemia 1 familial hypocalciuric hypercalcemia

Similar variants

CASR p.Arg441= 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
CASR c.493-2A>C Likely pathogenic ★★ same condition
CASR p.Ala581Val Likely pathogenic ★★ ⚠ same condition
CASR p.Ala835Asp Pathogenic/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-arg441lys (accessed [today's date]).

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