Is CASR p.Phe38= (c.114T>C) pathogenic?

CASR p.Phe38= (c.114T>C) is classified Conflicting classifications of pathogenicity in CASR (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-05-19). Ultra-rare (popmax 0.0164%, mid); Associated with familial hypocalciuric hypercalcemia.

What condition is associated with CASR p.Phe38= (c.114T>C)?

CASR p.Phe38= (c.114T>C) is associated with familial hypocalciuric hypercalcemia, autosomal dominant hypocalcemia 1 (ClinVar).

How common is CASR p.Phe38= (c.114T>C) in the general population?

CASR p.Phe38= (c.114T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Familial hypocalciuric hypercalcemia inherited?

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

CASR p.Phe38=

c.114T>C · rs61733590 · VCV193090

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

familial hypocalciuric hypercalcemia

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 0.47	GERP -3.3, phastCons 1
Overall
CADD	9.161	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00977% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00912%

Overall 0.00861% 139/1,614,048 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.0114%	8,806
African / African-American	0.00401%	24,967
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Phe38=
Coding: c.114T>C
MANE Select: NM_000388
dbSNP: rs61733590
Type: single nucleotide variant
Location: chr3:122254303 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 38: the 'ligand-binding 1 (lb1)' region; a β-strand

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.Phe38Leu Uncertain significance ★ ⚠ same residue
CASR p.Phe38fs Pathogenic ★ 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-phe38 (accessed [today's date]).

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