Is CASR p.Ser18Phe (c.53C>T) pathogenic?

CASR p.Ser18Phe (c.53C>T) is classified Uncertain significance in CASR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-27). AlphaMissense: likely benign (0.1325); Very rare (popmax 0.00223%, eas); Associated with familial hypocalciuric hypercalcemia.

What condition is associated with CASR p.Ser18Phe (c.53C>T)?

CASR p.Ser18Phe (c.53C>T) is associated with familial hypocalciuric hypercalcemia, familial hypocalciuric hypercalcemia 1, neonatal severe primary hyperparathyroidism (ClinVar).

How common is CASR p.Ser18Phe (c.53C>T) in the general population?

CASR p.Ser18Phe (c.53C>T) is very rare (popmax 0.00223%, eas) (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.Ser18Phe (c.53C>T)?

AlphaMissense predicts likely benign (score 0.1325) — an in-silico prediction, not a clinical call.

CASR p.Ser18Phe

c.53C>T · rs749748004 · VCV1350047

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1325 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypocalciuric hypercalcemia

Computational evidence

Protein change
AlphaMissense	0.1325	likely benign
REVEL	0.73	pathogenic-leaning
SaProt	LLR -7.49	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 59 bp · p 0.21 · regional, not allelic
Overall
CADD	22.3	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 0.00223% East Asian · 1/44,890 alleles

Overall 0.000124% 2/1,613,842 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
African / African-American	0.00134%	74,888

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.Ser18Phe
Coding: c.53C>T
MANE Select: NM_000388
dbSNP: rs749748004
Type: single nucleotide variant
Location: chr3:122254242 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB

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: familial hypocalciuric hypercalcemia 1 neonatal severe primary hyperparathyroidism autosomal dominant hypocalcemia 1 epilepsy, idiopathic generalized, susceptibility to, 8

For Familial hypocalciuric hypercalcemia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CASR p.Ser18= 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-ser18phe (accessed [today's date]).

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