Is CASR p.Arg701Ser (c.2101C>A) pathogenic?

CASR p.Arg701Ser (c.2101C>A) is classified Uncertain significance in CASR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-06). AlphaMissense: likely pathogenic (0.9817); Very rare (popmax 0.00267%, afr); Associated with familial hypocalciuric hypercalcemia.

What condition is associated with CASR p.Arg701Ser (c.2101C>A)?

CASR p.Arg701Ser (c.2101C>A) is associated with familial hypocalciuric hypercalcemia, familial hypocalciuric hypercalcemia 1, neonatal severe primary hyperparathyroidism (ClinVar).

How common is CASR p.Arg701Ser (c.2101C>A) in the general population?

CASR p.Arg701Ser (c.2101C>A) is very rare (popmax 0.00267%, afr) (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.Arg701Ser (c.2101C>A)?

AlphaMissense predicts likely pathogenic (score 0.9817) — an in-silico prediction, not a clinical call.

CASR p.Arg701Ser

c.2101C>A · rs757302986 · VCV1426376

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypocalciuric hypercalcemia

Computational evidence

Protein change
AlphaMissense	0.9817	likely pathogenic · top 9% in CASR
REVEL	0.69	pathogenic-leaning
SaProt	LLR -10.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 660 bp · p 1.4e-08 · regional, not allelic
Overall
CADD	22.7	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

Grpmax group 0.00267% African / African-American · 2/74,928 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,614,068 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,464
European (non-Finnish)	8.47e-05%	1,180,036

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.Arg701Ser
Coding: c.2101C>A
MANE Select: NM_000388
dbSNP: rs757302986
Type: single nucleotide variant
Location: chr3:122284055 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 701: a UniProt-annotated variant site (in hhc1; impaired homodimerization; impaired cell membrane localization); the 'intracellular loop 2 (icl2)' region; a turn

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.Arg701Cys Uncertain significance ★★ ⚠ same residue
CASR p.Arg701His Uncertain significance ★★ ⚠ same residue
CASR p.Arg701Leu Uncertain significance ★ ⚠ same residue
CASR p.Arg701= 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

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-arg701ser (accessed [today's date]).

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