Is IP6K3 p.Arg46Trp (c.136C>T) pathogenic?

IP6K3 p.Arg46Trp (c.136C>T) is classified Uncertain significance in IP6K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely benign (0.142); Very rare (popmax 0.00674%, amr).

How common is IP6K3 p.Arg46Trp (c.136C>T) in the general population?

IP6K3 p.Arg46Trp (c.136C>T) is very rare (popmax 0.00674%, amr) (gnomAD).

What do computational predictors say about IP6K3 p.Arg46Trp (c.136C>T)?

AlphaMissense predicts likely benign (score 0.142) — an in-silico prediction, not a clinical call.

IP6K3 p.Arg46Trp

c.136C>T · VCV4039124

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.142 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00674%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.142	likely benign
REVEL	0.462	indeterminate
SaProt	LLR -13.79	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP -0.29, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 13 kb · p 0.014 · regional, not allelic
Overall
CADD	25.8	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 0.00674% Admixed American · 4/59,320 alleles

Filtering AF 0.00227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00131% 21/1,607,380 alleles · very rare exomes 19/1,455,230 · genomes 2/152,150 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00674%	14,830
East Asian	0.00223%	44,810
South Asian	0.00221%	45,158
Remaining individualsnot grpmax-eligible	0.00161%	62,182
European (non-Finnish)	0.0011%	90,521

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.Arg46Trp
Coding: c.136C>T
MANE Select: NM_054111
Type: single nucleotide variant
Location: chr6:33735341 (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

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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
IP6K3 p.Arg185Cys 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-arg46trp (accessed [today's date]).

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