Is CASR p.Ile305= (c.915C>A) pathogenic?

CASR p.Ile305= (c.915C>A) is classified Benign/Likely benign in CASR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Rare (popmax 0.292%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CASR p.Ile305= (c.915C>A)?

CASR p.Ile305= (c.915C>A) is associated with hereditary neoplastic syndrome, familial hypocalciuric hypercalcemia 1, neonatal severe primary hyperparathyroidism (ClinVar).

How common is CASR p.Ile305= (c.915C>A) in the general population?

CASR p.Ile305= (c.915C>A) is rare (popmax 0.292%, eas) (gnomAD).

CASR p.Ile305=

c.915C>A · rs200528343 · VCV342796

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.292%, eas)

Conditions

hereditary neoplastic syndrome

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 -7	GERP -4.2
Overall
CADD	0.428	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.292% East Asian · 131/44,874 alleles

Filtering AF 0.251% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.236%

Overall 0.00966% 156/1,614,120 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.292%	343
South Asian	0.0198%	5,060
Remaining individualsnot grpmax-eligible	0.008%	12,501
Admixed American	0.00333%	30,015

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.Ile305=
Coding: c.915C>A
MANE Select: NM_000388
dbSNP: rs200528343
Type: single nucleotide variant
Location: chr3:122261950 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 305: the 'ligand-binding 2 (lb2)' region; a turn; a disulfide bond

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

Disease context

hereditary neoplastic syndrome — 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 familial hypoparathyroidism familial hypocalciuric hypercalcemia

Similar variants

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
CASR p.Arg172Gly 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-ile305 (accessed [today's date]).

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