Is IP6K2 p.Asp378Glu (c.1134T>G) pathogenic?

IP6K2 p.Asp378Glu (c.1134T>G) is classified Uncertain significance in IP6K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely pathogenic (0.8626); Ultra-rare (popmax 0.0102%, nfe).

How common is IP6K2 p.Asp378Glu (c.1134T>G) in the general population?

IP6K2 p.Asp378Glu (c.1134T>G) is ultra-rare (popmax 0.0102%, nfe) (gnomAD).

What do computational predictors say about IP6K2 p.Asp378Glu (c.1134T>G)?

AlphaMissense predicts likely pathogenic (score 0.8626) — an in-silico prediction, not a clinical call.

IP6K2 p.Asp378Glu

c.1134T>G · VCV4276095

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8626 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8626	likely pathogenic
REVEL	0.315	indeterminate
SaProt	LLR -6.19	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.29	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -3	GERP -4.9
Regional constraint	o/e 0.62	unconstrained · MANE · 7,015 bp · p 5.9e-19 · regional, not allelic
Overall
CADD	19.13	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 0.0102% European (non-Finnish) · 120/1,180,024 alleles

Filtering AF 0.00867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00781% 126/1,614,190 alleles · ultra-rare exomes 113/1,461,894 · genomes 13/152,296 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0102%	9,834
Remaining individualsnot grpmax-eligible	0.0064%	15,627
Admixed American	0.00167%	60,022
South Asian	0.0011%	91,078

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: IP6K2
Protein: p.Asp378Glu
Coding: c.1134T>G
MANE Select: NM_016291
Type: single nucleotide variant
Location: chr3:48688420 (GRCh38)
Gene constraint: LOEUF 0.385 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.92

Full IP6K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IP6K2 p.Ala195Gly Uncertain significance ★ ⚠ same type
IP6K2 p.Ala374Val Uncertain significance ★ ⚠ same type
IP6K2 p.Ala57Thr Uncertain significance ★ ⚠ same type
IP6K2 p.Arg133Cys Uncertain significance ★ ⚠ same type
IP6K2 p.Arg133His Uncertain significance ★ ⚠ same type
IP6K2 p.Arg198Gln Uncertain significance ★ ⚠ same type
IP6K2 p.Arg198Trp Uncertain significance ★ ⚠ same type
IP6K2 p.Arg212Cys 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/ip6k2-p-asp378glu (accessed [today's date]).

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