Is CASR p.Val504Leu (c.1510G>T) pathogenic?

CASR p.Val504Leu (c.1510G>T) is classified Uncertain significance in CASR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely benign (0.0945); Very rare (popmax 8.48e-05%, nfe); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with CASR p.Val504Leu (c.1510G>T)?

CASR p.Val504Leu (c.1510G>T) is associated with Nephrolithiasis/nephrocalcinosis (ClinVar).

How common is CASR p.Val504Leu (c.1510G>T) in the general population?

CASR p.Val504Leu (c.1510G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CASR p.Val504Leu (c.1510G>T)?

AlphaMissense predicts likely benign (score 0.0945) — an in-silico prediction, not a clinical call.

CASR p.Val504Leu

c.1510G>T · rs201536450 · VCV3231503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0945 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.0945	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -6.92	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	GERP -3.9
Regional constraint	o/e 0.78	unconstrained · MANE · 20 kb · p 1.6e-05 · regional, not allelic
Overall
CADD	1.937	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 8.48e-05% European (non-Finnish) · 1/1,179,910 alleles

Overall 6.84e-05% 1/1,461,730 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.Val504Leu
Coding: c.1510G>T
MANE Select: NM_000388
dbSNP: rs201536450
Type: single nucleotide variant
Location: chr3:122275944 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 504: 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

Similar variants

CASR p.Val504= Likely benign ★★ same residue
CASR p.Val504Gly Uncertain significance ★ ⚠ same residue
CASR p.Val504Met Conflicting classifications of pathogenicity ★ ⚠ same residue
CASR p.Arg465Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
CASR p.Glu767Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
CASR p.Ile555Thr Pathogenic/Likely pathogenic ★★ same condition
CASR p.Ala168Ser Uncertain significance ★★ ⚠ same condition
CASR p.Ala390Asp Uncertain significance ★★ ⚠ 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-val504leu (accessed [today's date]).

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