Is IPP p.Arg333Gln (c.998G>A) pathogenic?

IPP p.Arg333Gln (c.998G>A) is classified Uncertain significance in IPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-02). AlphaMissense: likely pathogenic (0.918); Ultra-rare (popmax 0.0135%, sas); Associated with IPP-related disorder.

What condition is associated with IPP p.Arg333Gln (c.998G>A)?

IPP p.Arg333Gln (c.998G>A) is associated with IPP-related disorder (ClinVar).

How common is IPP p.Arg333Gln (c.998G>A) in the general population?

IPP p.Arg333Gln (c.998G>A) is ultra-rare (popmax 0.0135%, sas) (gnomAD).

What do computational predictors say about IPP p.Arg333Gln (c.998G>A)?

AlphaMissense predicts likely pathogenic (score 0.918) — an in-silico prediction, not a clinical call.

IPP p.Arg333Gln

c.998G>A · VCV4854487

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.918 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

IPP-related disorder

Computational evidence

Protein change
AlphaMissense	0.918	likely pathogenic
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -14.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.041 · regional, not allelic
Overall
CADD	33.0	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 0.0135% South Asian · 12/88,696 alleles

Filtering AF 0.00779% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00608%

Overall 0.00163% 26/1,595,118 alleles · ultra-rare exomes 24/1,443,012 · genomes 2/152,106 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0135%	7,391
Remaining individualsnot grpmax-eligible	0.00162%	61,586
African / African-American	0.00134%	74,720
European (non-Finnish)	0.00103%	97,165

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: IPP
Protein: p.Arg333Gln
Coding: c.998G>A
MANE Select: NM_005897
Type: single nucleotide variant
Location: chr1:45727681 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.12

Full IPP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

IPP-related disorder

Similar variants

IPP p.Gly294Asp Uncertain significance ★ ⚠ same condition
IPP p.Ala203Gly Uncertain significance ★ ⚠ same type
IPP p.Ala204Val Uncertain significance ★ same type
IPP p.Ala374Val Uncertain significance ★ ⚠ same type
IPP p.Ala476Val Uncertain significance ★ ⚠ same type
IPP p.Ala524Val Uncertain significance ★ same type
IPP p.Ala57Ser Uncertain significance ★ ⚠ same type
IPP p.Arg283Trp 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/ipp-p-arg333gln (accessed [today's date]).

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