Is IP6K3 p.Arg366Cys (c.1096C>T) pathogenic?

IP6K3 p.Arg366Cys (c.1096C>T) is classified Uncertain significance in IP6K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-15). AlphaMissense: ambiguous (0.4521); Ultra-rare (popmax 0.0281%, nfe).

How common is IP6K3 p.Arg366Cys (c.1096C>T) in the general population?

IP6K3 p.Arg366Cys (c.1096C>T) is ultra-rare (popmax 0.0281%, nfe) (gnomAD).

What do computational predictors say about IP6K3 p.Arg366Cys (c.1096C>T)?

AlphaMissense predicts ambiguous (score 0.4521) — an in-silico prediction, not a clinical call.

IP6K3 p.Arg366Cys

c.1096C>T · rs146926476 · VCV2213025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4521 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0281%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4521	ambiguous
REVEL	0.443	indeterminate
SaProt	LLR -11.38	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.036, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 13 kb · p 0.014 · regional, not allelic
Overall
CADD	27.1	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 0.0281% European (non-Finnish) · 332/1,179,720 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.0237% 382/1,613,822 alleles · ultra-rare exomes 350/1,461,552 · genomes 32/152,270 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0468%	2,135
European (non-Finnish)grpmax	0.0281%	3,553
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Admixed American	0.005%	19,997
East Asian	0.00446%	22,439
African / African-American	0.00267%	37,518

Finnish 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: IP6K3
Protein: p.Arg366Cys
Coding: c.1096C>T
MANE Select: NM_054111
dbSNP: rs146926476
Type: single nucleotide variant
Location: chr6:33722857 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.40

Full IP6K3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IP6K3 p.Arg366His Uncertain significance ★ same residue
IP6K3 p.Gly26Arg Uncertain significance ★★ ⚠ same type
IP6K3 p.Ala124Asp Uncertain significance ★ ⚠ same type
IP6K3 p.Ala129Val Uncertain significance ★ ⚠ same type
IP6K3 p.Ala233Pro Uncertain significance ★ ⚠ same type
IP6K3 p.Ala7Thr Uncertain significance ★ ⚠ same type
IP6K3 p.Ala9Val Uncertain significance ★ ⚠ same type
IP6K3 p.Arg133Ser 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/ip6k3-p-arg366cys (accessed [today's date]).

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