Is IPP p.Arg464Cys (c.1390C>T) pathogenic?

IPP p.Arg464Cys (c.1390C>T) is classified Uncertain significance in IPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely benign (0.1088); Ultra-rare (popmax 0.0245%, eas).

How common is IPP p.Arg464Cys (c.1390C>T) in the general population?

IPP p.Arg464Cys (c.1390C>T) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about IPP p.Arg464Cys (c.1390C>T)?

AlphaMissense predicts likely benign (score 0.1088) — an in-silico prediction, not a clinical call.

IPP p.Arg464Cys

c.1390C>T · VCV3860988

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1088 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1088	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -7.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.041 · regional, not allelic
Overall
CADD	27.8	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 0.0245% East Asian · 11/44,880 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00217% 35/1,613,860 alleles · ultra-rare exomes 29/1,461,572 · genomes 6/152,288 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,080
Remaining individualsnot grpmax-eligible	0.0032%	31,249
European (non-Finnish)	0.0017%	58,988
Admixed American	0.00167%	60,018
African / African-American	0.00133%	75,030

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: IPP
Protein: p.Arg464Cys
Coding: c.1390C>T
MANE Select: NM_005897
Type: single nucleotide variant
Location: chr1:45714386 (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.Arg283Trp Uncertain significance ★ ⚠ same type
IPP p.Arg298Gln 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-arg464cys (accessed [today's date]).

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