Is IPP p.Arg409Leu (c.1226G>T) pathogenic?

IPP p.Arg409Leu (c.1226G>T) is classified Uncertain significance in IPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-23). AlphaMissense: ambiguous (0.3755); Very rare (popmax 0.00134%, afr).

How common is IPP p.Arg409Leu (c.1226G>T) in the general population?

IPP p.Arg409Leu (c.1226G>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about IPP p.Arg409Leu (c.1226G>T)?

AlphaMissense predicts ambiguous (score 0.3755) — an in-silico prediction, not a clinical call.

IPP p.Arg409Leu

c.1226G>T · VCV3860990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3755 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3755	ambiguous
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -11.32	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 0.81, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.041 · regional, not allelic
Overall
CADD	27.0	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 0.00134% African / African-American · 1/74,896 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,612,898 alleles · very rare exomes 2/1,460,790 · genomes 1/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,896
European (non-Finnish)	0.00017%	589,616

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.Arg409Leu
Coding: c.1226G>T
MANE Select: NM_005897
Type: single nucleotide variant
Location: chr1:45716978 (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-arg409leu (accessed [today's date]).

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