Is IP6K3 p.Pro55Leu (c.164C>T) pathogenic?

IP6K3 p.Pro55Leu (c.164C>T) is classified Uncertain significance in IP6K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely pathogenic (0.7616); Ultra-rare (popmax 0.0235%, amr).

How common is IP6K3 p.Pro55Leu (c.164C>T) in the general population?

IP6K3 p.Pro55Leu (c.164C>T) is ultra-rare (popmax 0.0235%, amr) (gnomAD).

What do computational predictors say about IP6K3 p.Pro55Leu (c.164C>T)?

AlphaMissense predicts likely pathogenic (score 0.7616) — an in-silico prediction, not a clinical call.

IP6K3 p.Pro55Leu

c.164C>T · rs757292142 · VCV2389871

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7616 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0235%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7616	likely pathogenic
REVEL	0.581	indeterminate
SaProt	LLR -10.37	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, 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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0235% Admixed American · 14/59,624 alleles

Filtering AF 0.0142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0113%

Overall 0.00279% 45/1,610,926 alleles · ultra-rare exomes 44/1,458,808 · genomes 1/152,118 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0235%	4,259
Remaining individualsnot grpmax-eligible	0.00321%	31,175
European (non-Finnish)	0.00246%	40,649

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.Pro55Leu
Coding: c.164C>T
MANE Select: NM_054111
dbSNP: rs757292142
Type: single nucleotide variant
Location: chr6:33735313 (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.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
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-pro55leu (accessed [today's date]).

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