Is CASR p.Val737Ile (c.2209G>A) pathogenic?

CASR p.Val737Ile (c.2209G>A) is classified Conflicting classifications of pathogenicity in CASR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0685); Very rare (popmax 0.00934%, afr); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with CASR p.Val737Ile (c.2209G>A)?

CASR p.Val737Ile (c.2209G>A) is associated with Nephrolithiasis/nephrocalcinosis, familial hypocalciuric hypercalcemia 1, neonatal severe primary hyperparathyroidism (ClinVar).

How common is CASR p.Val737Ile (c.2209G>A) in the general population?

CASR p.Val737Ile (c.2209G>A) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about CASR p.Val737Ile (c.2209G>A)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

CASR p.Val737Ile

c.2209G>A · rs200318708 · VCV572425

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -6.11	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 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 660 bp · p 1.4e-08 · regional, not allelic
Overall
CADD	20.7	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 0.00934% African / African-American · 7/74,912 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000434% 7/1,613,376 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.Val737Ile
Coding: c.2209G>A
MANE Select: NM_000388
dbSNP: rs200318708
Type: single nucleotide variant
Location: chr3:122284163 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 737: a UniProt-annotated variant site (in hhc1; impaired homodimerization; impaired cell membrane localization); an α-helix

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.Val737= 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-val737ile (accessed [today's date]).

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