Is ITPR3 p.Arg1682= (c.5046G>C) pathogenic?

ITPR3 p.Arg1682= (c.5046G>C) is classified Uncertain significance in ITPR3 (ClinVar, Single submitter, 1 submitter). Ultra-rare (popmax 0.0164%, mid); Associated with Charcot-Marie-Tooth disease, demyelinating, type 1J.

What condition is associated with ITPR3 p.Arg1682= (c.5046G>C)?

ITPR3 p.Arg1682= (c.5046G>C) is associated with Charcot-Marie-Tooth disease, demyelinating, type 1J (ClinVar).

How common is ITPR3 p.Arg1682= (c.5046G>C) in the general population?

ITPR3 p.Arg1682= (c.5046G>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

ITPR3 p.Arg1682=

c.5046G>C · VCV4537403

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Charcot-Marie-Tooth disease, demyelinating, type 1J

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.41	donor gain · deltas
Pangolin	Δ0.23	gain · loss 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5	GERP 2.4, phastCons 1
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00136% 22/1,613,638 alleles · ultra-rare exomes 19/1,461,466 · genomes 3/152,172 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Finnishnot grpmax-eligible	0.0156%	6,401
South Asian	0.00439%	22,767
European (non-Finnish)	0.000593%	168,533

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: ITPR3
Protein: p.Arg1682=
Coding: c.5046G>C
MANE Select: NM_002224
Type: single nucleotide variant
Location: chr6:33684465 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.04 · 24 PDB
Residue 1682: an α-helix

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

Disease context

Charcot-Marie-Tooth disease, demyelinating, type 1J — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ITPR3 p.Arg1682Gln Uncertain significance ★ ⚠ same residue
ITPR3 p.Arg1682Trp Uncertain significance ★ ⚠ same residue
ITPR3 p.Thr1424Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
ITPR3 p.Ala1352Thr Uncertain significance ★★ ⚠ same condition
ITPR3 p.Arg1085Leu Uncertain significance ★★ ⚠ same condition
ITPR3 p.Asp1968Val Uncertain significance ★★ ⚠ same condition
ITPR3 p.Glu669Asp Uncertain significance ★★ ⚠ same condition
ITPR3 p.His359Arg Uncertain significance ★★ ⚠ 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-arg1682 (accessed [today's date]).

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