Is IP6K3 p.Pro211Ser (c.631C>T) pathogenic?

IP6K3 p.Pro211Ser (c.631C>T) is classified Uncertain significance in IP6K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely pathogenic (0.9164); Very rare (popmax 0.00266%, afr).

How common is IP6K3 p.Pro211Ser (c.631C>T) in the general population?

IP6K3 p.Pro211Ser (c.631C>T) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about IP6K3 p.Pro211Ser (c.631C>T)?

AlphaMissense predicts likely pathogenic (score 0.9164) — an in-silico prediction, not a clinical call.

IP6K3 p.Pro211Ser

c.631C>T · VCV4679208

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9164	likely pathogenic
REVEL	0.536	indeterminate
SaProt	LLR -11.01	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 9.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 13 kb · p 0.014 · regional, not allelic
Overall
CADD	26.5	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 0.00266% African / African-American · 2/75,062 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,614,210 alleles · very rare exomes 3/1,461,854 · genomes 0/152,356 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00266%	37,531
Admixed American	0.00167%	60,030

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.Pro211Ser
Coding: c.631C>T
MANE Select: NM_054111
Type: single nucleotide variant
Location: chr6:33725575 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.40
Residue 211: a binding site

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-pro211ser (accessed [today's date]).

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