Is IP6K2 p.Arg133Cys (c.397C>T) pathogenic?

IP6K2 p.Arg133Cys (c.397C>T) is classified Uncertain significance in IP6K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-12). AlphaMissense: likely benign (0.2449); Very rare (popmax 0.00445%, eas).

How common is IP6K2 p.Arg133Cys (c.397C>T) in the general population?

IP6K2 p.Arg133Cys (c.397C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about IP6K2 p.Arg133Cys (c.397C>T)?

AlphaMissense predicts likely benign (score 0.2449) — an in-silico prediction, not a clinical call.

IP6K2 p.Arg133Cys

c.397C>T · rs575264529 · VCV3110278

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2449 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2449	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.3	GERP 0.61, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 7,015 bp · p 5.9e-19 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,894 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00031% 5/1,613,888 alleles · very rare exomes 3/1,461,540 · genomes 2/152,348 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,447
European (non-Finnish)	0.000254%	393,281

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.Arg133Cys
Coding: c.397C>T
MANE Select: NM_016291
dbSNP: rs575264529
Type: single nucleotide variant
Location: chr3:48692985 (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.Arg133His Uncertain significance ★ ⚠ same residue
IP6K2 p.Ala195Gly Uncertain significance ★ ⚠ same type
IP6K2 p.Ala374Val Uncertain significance ★ ⚠ same type
IP6K2 p.Ala57Thr 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
IP6K2 p.Arg212His 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-arg133cys (accessed [today's date]).

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