Is ITPR1 p.Leu536Phe (c.1606C>T) pathogenic?

ITPR1 p.Leu536Phe (c.1606C>T) is classified Likely benign in ITPR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-02-09). AlphaMissense: likely pathogenic (0.95); Very rare (popmax 0.00017%, nfe); Associated with spinocerebellar ataxia type 29.

What condition is associated with ITPR1 p.Leu536Phe (c.1606C>T)?

ITPR1 p.Leu536Phe (c.1606C>T) is associated with spinocerebellar ataxia type 29 (ClinVar).

How common is ITPR1 p.Leu536Phe (c.1606C>T) in the general population?

ITPR1 p.Leu536Phe (c.1606C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Spinocerebellar ataxia type 29 inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ITPR1 p.Leu536Phe (c.1606C>T)?

AlphaMissense predicts likely pathogenic (score 0.95) — an in-silico prediction, not a clinical call.

ITPR1 p.Leu536Phe

c.1606C>T · rs1553681680 · VCV503528

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.95 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

spinocerebellar ataxia type 29

Computational evidence

Protein change
AlphaMissense	0.95	likely pathogenic
REVEL	0.702	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 18 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,856 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,012 alleles · very rare exomes 2/1,461,664 · genomes 0/152,348 · 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: ITPR1
Protein: p.Leu536Phe
Coding: c.1606C>T
MANE Select: NM_001378452
dbSNP: rs1553681680
Type: single nucleotide variant
Location: chr3:4665189 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)

Full ITPR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spinocerebellar ataxia type 29 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spinocerebellar ataxia type 29 (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ITPR1 p.Arg241Lys Pathogenic/Likely pathogenic ★★ same condition
ITPR1 p.Arg269Trp Pathogenic/Likely pathogenic ★★ same condition
ITPR1 p.Arg504Gly Likely pathogenic ★★ same condition
ITPR1 p.Arg511Gly Likely pathogenic ★★ same condition
ITPR1 p.Arg511Ser Likely pathogenic ★★ same condition
ITPR1 p.Gly2554Arg Pathogenic/Likely pathogenic ★★ same condition
ITPR1 p.Ile2598Thr Pathogenic/Likely pathogenic ★★ same condition
ITPR1 p.Thr2434Ile 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/itpr1-p-leu536phe (accessed [today's date]).

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