Is CASR p.Val337= (c.1011C>G) pathogenic?

CASR p.Val337= (c.1011C>G) is classified Conflicting classifications of pathogenicity in CASR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-06). Ultra-rare (popmax 0.0791%, sas); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with CASR p.Val337= (c.1011C>G)?

CASR p.Val337= (c.1011C>G) is associated with Nephrolithiasis/nephrocalcinosis, familial hypocalciuric hypercalcemia 1, neonatal severe primary hyperparathyroidism (ClinVar).

How common is CASR p.Val337= (c.1011C>G) in the general population?

CASR p.Val337= (c.1011C>G) is ultra-rare (popmax 0.0791%, sas) (gnomAD).

CASR p.Val337=

c.1011C>G · rs201820733 · VCV463888

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0791%, sas)

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.081	GERP -2.2, phastCons 0.37
Overall
CADD	4.365	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0791% South Asian · 72/91,076 alleles

Filtering AF 0.0643% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.059%

Overall 0.00508% 82/1,614,150 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0791%	1,265
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0064%	15,627
African / African-American	0.00133%	75,026
European (non-Finnish)	0.000254%	393,345

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.Val337=
Coding: c.1011C>G
MANE Select: NM_000388
dbSNP: rs201820733
Type: single nucleotide variant
Location: chr3:122262046 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 337: 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: familial hypocalciuric hypercalcemia 1 neonatal severe primary hyperparathyroidism autosomal dominant hypocalcemia 1 epilepsy, idiopathic generalized, susceptibility to, 8 familial hypocalciuric hypercalcemia

Similar variants

CASR p.Val337Phe Uncertain significance ★★ ⚠ same residue
CASR p.Val337Ala Uncertain significance ★ ⚠ 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

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-val337 (accessed [today's date]).

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