Is CASR p.Phe862Ser (c.2585T>C) pathogenic?

CASR p.Phe862Ser (c.2585T>C) is classified Conflicting classifications of pathogenicity in CASR (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-03). AlphaMissense: likely pathogenic (0.6296); Ultra-rare (popmax 0.0659%, sas); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with CASR p.Phe862Ser (c.2585T>C)?

CASR p.Phe862Ser (c.2585T>C) is associated with Nephrolithiasis/nephrocalcinosis, familial hypocalciuric hypercalcemia 1, autosomal dominant hypocalcemia 1 (ClinVar).

How common is CASR p.Phe862Ser (c.2585T>C) in the general population?

CASR p.Phe862Ser (c.2585T>C) is ultra-rare (popmax 0.0659%, sas) (gnomAD).

What do computational predictors say about CASR p.Phe862Ser (c.2585T>C)?

AlphaMissense predicts likely pathogenic (score 0.6296) — an in-silico prediction, not a clinical call.

CASR p.Phe862Ser

c.2585T>C · rs201328344 · VCV532619

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6296 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0659%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.6296	likely pathogenic
REVEL	0.89	moderately pathogenic-leaning
SaProt	LLR -11.11	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 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 153 bp · p 0.00027 · regional, not allelic
Overall
CADD	27.3	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 0.0659% South Asian · 60/91,092 alleles

Filtering AF 0.0525% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0476%

Overall 0.00415% 67/1,613,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0659%	1,518
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.000254%	393,352

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.Phe862Ser
Coding: c.2585T>C
MANE Select: NM_000388
dbSNP: rs201328344
Type: single nucleotide variant
Location: chr3:122284539 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 862: a UniProt-annotated variant site (in hhc1; impaired homodimerization; impaired cell membrane localization); the 'c-terminus' region; an α-helix

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

Disease context

Nephrolithiasis/nephrocalcinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypocalciuric hypercalcemia 1 autosomal dominant hypocalcemia 1 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-phe862ser (accessed [today's date]).

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