Is ITPR2 p.Leu1049Phe (c.3145C>T) pathogenic?

ITPR2 p.Leu1049Phe (c.3145C>T) is classified Uncertain significance in ITPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: likely pathogenic (0.8228); Very rare (popmax 0.00113%, sas).

How common is ITPR2 p.Leu1049Phe (c.3145C>T) in the general population?

ITPR2 p.Leu1049Phe (c.3145C>T) is very rare (popmax 0.00113%, sas) (gnomAD).

What do computational predictors say about ITPR2 p.Leu1049Phe (c.3145C>T)?

AlphaMissense predicts likely pathogenic (score 0.8228) — an in-silico prediction, not a clinical call.

ITPR2 p.Leu1049Phe

c.3145C>T · VCV4040441

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8228 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, sas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.8228	likely pathogenic
REVEL	0.223	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 61 kb · p 0.0071 · regional, not allelic
Overall
CADD	26.5	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 0.00113% South Asian · 1/88,840 alleles

Overall 6.24e-05% 1/1,603,840 alleles · very rare exomes 1/1,451,554 · genomes 0/152,286 · 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: ITPR2
Protein: p.Leu1049Phe
Coding: c.3145C>T
MANE Select: NM_002223
Type: single nucleotide variant
Location: chr12:26622383 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)

Full ITPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ITPR2 p.Val1162Gly Uncertain significance ★★ same type
ITPR2 c.3801+23G>A Benign ★★ same type
ITPR2 c.5073+10T>A Benign ★★ same type
ITPR2 c.93-10T>A Benign ★★ same type
ITPR2 p.Ala1898Val Benign ★★ same type
ITPR2 p.Arg1180Gln Likely benign ★★ same type
ITPR2 p.Arg1275Gln Likely benign ★★ same type
ITPR2 p.Asn461= Benign ★★ 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/itpr2-p-leu1049phe (accessed [today's date]).

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