Is CASR p.Ser899Pro (c.2695T>C) pathogenic?

CASR p.Ser899Pro (c.2695T>C) is classified Uncertain significance in CASR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-31). AlphaMissense: likely benign (0.0912); Very rare (popmax 0.000254%, nfe); Associated with autosomal dominant hypocalcemia 1.

What condition is associated with CASR p.Ser899Pro (c.2695T>C)?

CASR p.Ser899Pro (c.2695T>C) is associated with autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia (ClinVar).

How common is CASR p.Ser899Pro (c.2695T>C) in the general population?

CASR p.Ser899Pro (c.2695T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CASR p.Ser899Pro (c.2695T>C)?

AlphaMissense predicts likely benign (score 0.0912) — an in-silico prediction, not a clinical call.

CASR p.Ser899Pro

c.2695T>C · rs201919386 · VCV644476

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0912 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal dominant hypocalcemia 1

Computational evidence

Protein change
AlphaMissense	0.0912	likely benign
REVEL	0.578	indeterminate
SaProt	LLR -7.65	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 554 bp · p 0.066 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000254% European (non-Finnish) · 3/1,179,898 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,726 alleles · very rare

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.Ser899Pro
Coding: c.2695T>C
MANE Select: NM_000388
dbSNP: rs201919386
Type: single nucleotide variant
Location: chr3:122284649 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 899: a UniProt-annotated variant site (in hhc1; impaired homodimerization; impaired cell membrane localization); the 'c-terminus' region; the 'interaction with rnf19a' region; the 'disordered' region; a modified residue (phosphoserine; by pka)

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

Similar variants

CASR p.Ser899Cys Uncertain significance ★ ⚠ same residue
CASR p.Ser899= 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

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-ser899pro (accessed [today's date]).

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