Is CASR p.Ser247Phe (c.740C>T) pathogenic?

CASR p.Ser247Phe (c.740C>T) is classified Conflicting classifications of pathogenicity in CASR (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.2096); Ultra-rare (popmax 0.033%, mid); Associated with autosomal dominant hypocalcemia 1.

What condition is associated with CASR p.Ser247Phe (c.740C>T)?

CASR p.Ser247Phe (c.740C>T) is associated with autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia 1, neonatal severe primary hyperparathyroidism (ClinVar).

How common is CASR p.Ser247Phe (c.740C>T) in the general population?

CASR p.Ser247Phe (c.740C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about CASR p.Ser247Phe (c.740C>T)?

AlphaMissense predicts likely benign (score 0.2096) — an in-silico prediction, not a clinical call.

CASR p.Ser247Phe

c.740C>T · rs200382161 · VCV64438

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2096 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant hypocalcemia 1

Computational evidence

Protein change
AlphaMissense	0.2096	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -7.01	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 7.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 20 kb · p 1.6e-05 · regional, not allelic
Overall
CADD	20.8	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00582% 94/1,614,220 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Finnishnot grpmax-eligible	0.0141%	7,115
South Asian	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.0064%	15,628
European (non-Finnish)	0.00551%	18,154
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
African / African-American	0.00266%	37,530
Admixed American	0.00167%	60,030

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.Ser247Phe
Coding: c.740C>T
MANE Select: NM_000388
dbSNP: rs200382161
Type: single nucleotide variant
Location: chr3:122261775 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 247: the 'ligand-binding 2 (lb2)' region; a disulfide bond

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

Disease context

autosomal dominant hypocalcemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypocalciuric hypercalcemia 1 neonatal severe primary hyperparathyroidism epilepsy, idiopathic generalized, susceptibility to, 8 familial hypocalciuric hypercalcemia

Similar variants

CASR p.Ser247Ala Uncertain significance ★ ⚠ same residue
CASR p.Ser247Cys Uncertain significance ★ ⚠ 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-ser247phe (accessed [today's date]).

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