Is IP6K2 p.Val343Ala (c.1028T>C) pathogenic?

IP6K2 p.Val343Ala (c.1028T>C) is classified Uncertain significance in IP6K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0683); Ultra-rare (popmax 0.0297%, nfe).

How common is IP6K2 p.Val343Ala (c.1028T>C) in the general population?

IP6K2 p.Val343Ala (c.1028T>C) is ultra-rare (popmax 0.0297%, nfe) (gnomAD).

What do computational predictors say about IP6K2 p.Val343Ala (c.1028T>C)?

AlphaMissense predicts likely benign (score 0.0683) — an in-silico prediction, not a clinical call.

IP6K2 p.Val343Ala

c.1028T>C · VCV4039119

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0683 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0297%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0683	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 7,015 bp · p 5.9e-19 · regional, not allelic
Overall
CADD	19.42	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 0.0297% European (non-Finnish) · 351/1,180,048 alleles

Filtering AF 0.0271% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0262%

Overall 0.0227% 367/1,614,096 alleles · ultra-rare exomes 356/1,461,894 · genomes 11/152,202 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0297%	3,362
Remaining individualsnot grpmax-eligible	0.0144%	6,943
African / African-American	0.00534%	18,730
Finnishnot grpmax-eligible	0.00312%	32,020
South Asian	0.0011%	91,090

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.Val343Ala
Coding: c.1028T>C
MANE Select: NM_016291
Type: single nucleotide variant
Location: chr3:48688526 (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-val343ala (accessed [today's date]).

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