Is ITPR2 p.Ser228Phe (c.683C>T) pathogenic?

ITPR2 p.Ser228Phe (c.683C>T) is classified Uncertain significance in ITPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-06). AlphaMissense: likely benign (0.2087); Very rare (popmax 0.000937%, nfe).

How common is ITPR2 p.Ser228Phe (c.683C>T) in the general population?

ITPR2 p.Ser228Phe (c.683C>T) is very rare (popmax 0.000937%, nfe) (gnomAD).

What do computational predictors say about ITPR2 p.Ser228Phe (c.683C>T)?

AlphaMissense predicts likely benign (score 0.2087) — an in-silico prediction, not a clinical call.

ITPR2 p.Ser228Phe

c.683C>T · rs868019660 · VCV2494616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000937%, nfe)

Computational evidence

Protein change
AlphaMissense	0.2087	likely benign
REVEL	0.527	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.45, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 175 kb · p 1.6e-22 · regional, not allelic
Overall
CADD	26.6	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 0.000937% European (non-Finnish) · 11/1,173,952 alleles

Filtering AF 0.000503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000368%

Overall 0.000747% 12/1,606,690 alleles · very rare exomes 12/1,454,522 · genomes 0/152,168 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,248
European (non-Finnish)grpmax	0.000937%	106,723

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser228Phe
Coding: c.683C>T
MANE Select: NM_002223
dbSNP: rs868019660
Type: single nucleotide variant
Location: chr12:26715777 (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-ser228phe (accessed [today's date]).

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