Is IP6K3 p.Arg366His (c.1097G>A) pathogenic?

IP6K3 p.Arg366His (c.1097G>A) is classified Uncertain significance in IP6K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: ambiguous (0.4692); Ultra-rare (popmax 0.0107%, afr).

How common is IP6K3 p.Arg366His (c.1097G>A) in the general population?

IP6K3 p.Arg366His (c.1097G>A) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about IP6K3 p.Arg366His (c.1097G>A)?

AlphaMissense predicts ambiguous (score 0.4692) — an in-silico prediction, not a clinical call.

IP6K3 p.Arg366His

c.1097G>A · rs748608668 · VCV2484059

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4692 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Computational evidence

Protein change
AlphaMissense	0.4692	ambiguous
REVEL	0.415	indeterminate
SaProt	LLR -11.33	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 13 kb · p 0.014 · regional, not allelic
Overall
CADD	28.6	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 0.0107% African / African-American · 8/74,900 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00124% 20/1,613,584 alleles · ultra-rare exomes 13/1,461,496 · genomes 7/152,088 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,363
Admixed American	0.005%	19,985
East Asian	0.00223%	44,884
South Asian	0.0022%	45,541
European (non-Finnish)	0.000509%	196,610

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.Arg366His
Coding: c.1097G>A
MANE Select: NM_054111
dbSNP: rs748608668
Type: single nucleotide variant
Location: chr6:33722856 (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.Arg366Cys 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-arg366his (accessed [today's date]).

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