Is ITPR3 p.Ser620Arg (c.1860C>A) pathogenic?

ITPR3 p.Ser620Arg (c.1860C>A) is classified Uncertain significance in ITPR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-06). AlphaMissense: likely pathogenic (0.7271); Very rare (popmax 0.000558%).

How common is ITPR3 p.Ser620Arg (c.1860C>A) in the general population?

ITPR3 p.Ser620Arg (c.1860C>A) is very rare (popmax 0.000558%) (gnomAD).

What do computational predictors say about ITPR3 p.Ser620Arg (c.1860C>A)?

AlphaMissense predicts likely pathogenic (score 0.7271) — an in-silico prediction, not a clinical call.

ITPR3 p.Ser620Arg

c.1860C>A · VCV3287007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7271 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000558%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7271	likely pathogenic
REVEL	0.844	moderately pathogenic-leaning
SaProt	LLR -7.76	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 2.2	GERP -1.1, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 14 kb · p 5e-11 · regional, not allelic
Overall
CADD	26.0	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 0.000558%

Overall 0.000558% 9/1,614,224 alleles · very rare exomes 9/1,461,864 · genomes 0/152,360 · 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.Ser620Arg
Coding: c.1860C>A
MANE Select: NM_002224
Type: single nucleotide variant
Location: chr6:33667938 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.04 · 24 PDB
Residue 620: an α-helix

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

Similar variants

ITPR3 p.Thr1424Met Pathogenic/Likely pathogenic ★★ ⚠ same type
ITPR3 p.Ala1352Thr Uncertain significance ★★ ⚠ same type
ITPR3 p.Arg1085Leu Uncertain significance ★★ ⚠ same type
ITPR3 p.Arg2659Cys Uncertain significance ★★ ⚠ same type
ITPR3 p.Asp1968Val Uncertain significance ★★ ⚠ same type
ITPR3 p.Glu669Asp Uncertain significance ★★ ⚠ same type
ITPR3 p.Gly1008Trp Uncertain significance ★★ ⚠ same type
ITPR3 p.Gly2514Glu Uncertain significance ★★ ⚠ 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/itpr3-p-ser620arg (accessed [today's date]).

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