Is ITPR3 p.Ser563Cys (c.1688C>G) pathogenic?

ITPR3 p.Ser563Cys (c.1688C>G) is classified Uncertain significance in ITPR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-19). AlphaMissense: likely pathogenic (0.6365); Absent from gnomAD v4.1; Associated with immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy.

How common is ITPR3 p.Ser563Cys (c.1688C>G) in the general population?

ITPR3 p.Ser563Cys (c.1688C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ITPR3 p.Ser563Cys (c.1688C>G)?

AlphaMissense predicts likely pathogenic (score 0.6365) — an in-silico prediction, not a clinical call.

ITPR3 p.Ser563Cys

Q: What condition is associated with ITPR3 p.Ser563Cys (c.1688C>G)?

ITPR3 p.Ser563Cys (c.1688C>G) is associated with immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy (ClinVar).

c.1688C>G · VCV4850951

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6365 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy

Computational evidence

Protein change
AlphaMissense	0.6365	likely pathogenic
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -9.35	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 14 kb · p 5e-11 · regional, not allelic
Overall
CADD	28.8	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

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: ITPR3
Protein: p.Ser563Cys
Coding: c.1688C>G
MANE Select: NM_002224
Type: single nucleotide variant
Location: chr6:33667265 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.04 · 24 PDB
Residue 563: a turn

Full ITPR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ITPR3 p.Arg2524His Likely pathogenic ★ same condition
ITPR3 c.1148+10C>T Conflicting classifications of pathogenicity ★ same condition
ITPR3 p.Arg2524Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
ITPR3 p.Arg503Trp Uncertain significance ★ ⚠ same condition
ITPR3 p.Glu1639Lys Uncertain significance ★ ⚠ same condition
ITPR3 p.Leu476Pro Uncertain significance ★ ⚠ same condition
ITPR3 p.Arg1850Gln Benign ★ same condition
ITPR3 p.Ala196Thr 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/itpr3-p-ser563cys (accessed [today's date]).

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