Is CASR p.Cys765Trp (c.2295C>G) pathogenic?

CASR p.Cys765Trp (c.2295C>G) is classified Uncertain significance in CASR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-22). AlphaMissense: likely pathogenic (0.996); Absent from gnomAD v4.1.

How common is CASR p.Cys765Trp (c.2295C>G) in the general population?

CASR p.Cys765Trp (c.2295C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASR p.Cys765Trp (c.2295C>G)?

AlphaMissense predicts likely pathogenic (score 0.996) — an in-silico prediction, not a clinical call.

CASR p.Cys765Trp

c.2295C>G · rs1232096655 · VCV1098780

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.996	likely pathogenic · top 4% in CASR
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -15.09	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 2.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 660 bp · p 1.4e-08 · regional, not allelic
Overall
CADD	28.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CASR
Protein: p.Cys765Trp
Coding: c.2295C>G
MANE Select: NM_000388
dbSNP: rs1232096655
Type: single nucleotide variant
Location: chr3:122284249 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.01 · 31 PDB
Residue 765: a UniProt-annotated variant site (in hhc1; impaired homodimerization; impaired cell membrane localization); a β-strand

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

Similar variants

CASR p.Cys765= Likely benign ★★ same residue
CASR p.Cys765Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CASR p.Cys765_Leu770delinsTrpAlaIleIlePhe Likely pathogenic ★ same residue
CASR p.Cys765fs Likely pathogenic ★ same residue
CASR c.1378-1G>C Likely pathogenic ★★ same type
CASR c.1608+1G>A Likely pathogenic ★★ same type
CASR c.1609-2A>G Likely pathogenic ★★ same type
CASR c.1732+1G>T Pathogenic/Likely pathogenic ★★ same type

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-cys765trp (accessed [today's date]).

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