Is IP6K3 p.Val71Ala (c.212T>C) pathogenic?

IP6K3 p.Val71Ala (c.212T>C) is classified Uncertain significance in IP6K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.6849); Ultra-rare (popmax 0.0124%, nfe).

How common is IP6K3 p.Val71Ala (c.212T>C) in the general population?

IP6K3 p.Val71Ala (c.212T>C) is ultra-rare (popmax 0.0124%, nfe) (gnomAD).

What do computational predictors say about IP6K3 p.Val71Ala (c.212T>C)?

AlphaMissense predicts likely pathogenic (score 0.6849) — an in-silico prediction, not a clinical call.

IP6K3 p.Val71Ala

c.212T>C · rs751829854 · VCV2596344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6849 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0124%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6849	likely pathogenic
REVEL	0.283	benign-leaning
SaProt	LLR -10.15	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 13 kb · p 0.014 · regional, not allelic
Overall
CADD	25.0	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 0.0124% European (non-Finnish) · 146/1,180,010 alleles

Filtering AF 0.0107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.01%

Overall 0.00929% 150/1,614,158 alleles · ultra-rare exomes 136/1,461,844 · genomes 14/152,314 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0124%	8,082
Remaining individualsnot grpmax-eligible	0.0048%	20,837
African / African-American	0.00133%	75,062

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.Val71Ala
Coding: c.212T>C
MANE Select: NM_054111
dbSNP: rs751829854
Type: single nucleotide variant
Location: chr6:33728288 (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-val71ala (accessed [today's date]).

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