Is ITPR3 p.Arg149Trp (c.445C>T) pathogenic?

ITPR3 p.Arg149Trp (c.445C>T) is classified Conflicting classifications of pathogenicity in ITPR3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-10). AlphaMissense: likely pathogenic (0.9831); Very rare (popmax 8.47e-05%, nfe); Associated with Charcot-Marie-Tooth disease, demyelinating, type 1J.

What condition is associated with ITPR3 p.Arg149Trp (c.445C>T)?

ITPR3 p.Arg149Trp (c.445C>T) is associated with Charcot-Marie-Tooth disease, demyelinating, type 1J (ClinVar).

How common is ITPR3 p.Arg149Trp (c.445C>T) in the general population?

ITPR3 p.Arg149Trp (c.445C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ITPR3 p.Arg149Trp (c.445C>T)?

AlphaMissense predicts likely pathogenic (score 0.9831) — an in-silico prediction, not a clinical call.

ITPR3 p.Arg149Trp

c.445C>T · rs1237600471 · VCV2578246

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9831	likely pathogenic
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -14.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.46	GERP -4.3, phastCons 0.99
Regional constraint	o/e 0.62	unconstrained · MANE · 6,740 bp · p 1.1e-08 · regional, not allelic
Overall
CADD	25.5	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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.2e-05% 1/1,614,194 alleles · very rare exomes 1/1,461,852 · genomes 0/152,342 · joint denominator

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.Arg149Trp
Coding: c.445C>T
MANE Select: NM_002224
dbSNP: rs1237600471
Type: single nucleotide variant
Location: chr6:33658745 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.04 · 24 PDB
Residue 149: the mir 1 domain; a β-strand

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.Arg149Gln 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
ITPR3 p.Arg2524Ser 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/itpr3-p-arg149trp (accessed [today's date]).

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