Is IPP p.Arg283Trp (c.847C>T) pathogenic?

IPP p.Arg283Trp (c.847C>T) is classified Uncertain significance in IPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.9783); Ultra-rare (popmax 0.0116%, nfe).

How common is IPP p.Arg283Trp (c.847C>T) in the general population?

IPP p.Arg283Trp (c.847C>T) is ultra-rare (popmax 0.0116%, nfe) (gnomAD).

What do computational predictors say about IPP p.Arg283Trp (c.847C>T)?

AlphaMissense predicts likely pathogenic (score 0.9783) — an in-silico prediction, not a clinical call.

IPP p.Arg283Trp

c.847C>T · VCV4276222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9783 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0116%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9783	likely pathogenic · top 7% in IPP
REVEL	0.628	indeterminate
SaProt	LLR -13.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.041 · regional, not allelic
Overall
CADD	28.7	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 0.0116% European (non-Finnish) · 137/1,179,572 alleles

Filtering AF 0.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0094%

Overall 0.00905% 146/1,613,014 alleles · ultra-rare exomes 137/1,460,862 · genomes 9/152,152 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0116%	8,610
Remaining individualsnot grpmax-eligible	0.00961%	10,410
East Asian	0.00223%	44,780
African / African-American	0.00133%	74,966
South Asian	0.0011%	90,854

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.Arg283Trp
Coding: c.847C>T
MANE Select: NM_005897
Type: single nucleotide variant
Location: chr1:45729647 (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

Similar variants

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.Arg298Gln Uncertain significance ★ ⚠ same type
IPP p.Arg298Trp 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-arg283trp (accessed [today's date]).

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