Is CASR p.Phe239Val (c.715T>G) pathogenic?

CASR p.Phe239Val (c.715T>G) is classified Uncertain significance in CASR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-08). AlphaMissense: likely pathogenic (0.9123); Absent from gnomAD v4.1; Associated with familial hypocalciuric hypercalcemia.

What condition is associated with CASR p.Phe239Val (c.715T>G)?

CASR p.Phe239Val (c.715T>G) is associated with familial hypocalciuric hypercalcemia, autosomal dominant hypocalcemia 1 (ClinVar).

How common is CASR p.Phe239Val (c.715T>G) in the general population?

CASR p.Phe239Val (c.715T>G) is absent from gnomAD v4.1 (gnomAD).

How is Familial hypocalciuric hypercalcemia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CASR p.Phe239Val (c.715T>G)?

AlphaMissense predicts likely pathogenic (score 0.9123) — an in-silico prediction, not a clinical call.

CASR p.Phe239Val

c.715T>G · rs2473226130 · VCV2936084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9123 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial hypocalciuric hypercalcemia

Computational evidence

Protein change
AlphaMissense	0.9123	likely pathogenic
REVEL	0.624	indeterminate
SaProt	LLR -13.98	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 7,518 bp · p 3.2e-17 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CASR
Protein: p.Phe239Val
Coding: c.715T>G
MANE Select: NM_000388
dbSNP: rs2473226130
Type: single nucleotide variant
Location: chr3:122261750 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 239: the 'ligand-binding 2 (lb2)' region; a β-strand; a disulfide bond

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

Disease context

familial hypocalciuric hypercalcemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant hypocalcemia 1

For Familial hypocalciuric hypercalcemia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CASR p.Phe239= 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-phe239val (accessed [today's date]).

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