Is IVD p.Pro217fs (c.650del) pathogenic?

IVD p.Pro217fs (c.650del) is classified Pathogenic/Likely pathogenic in IVD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-24). Very rare (popmax 0.00133%, afr); Associated with isovaleric acidemia.

What condition is associated with IVD p.Pro217fs (c.650del)?

IVD p.Pro217fs (c.650del) is associated with isovaleric acidemia (ClinVar).

How common is IVD p.Pro217fs (c.650del) in the general population?

IVD p.Pro217fs (c.650del) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Isovaleric acidemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

IVD p.Pro217fs

c.650del · rs1364046355 · VCV593628

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

isovaleric acidemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.67	GERP 1.4, phastCons 0.79
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,932 alleles

Overall 6.2e-05% 1/1,614,110 alleles · very rare exomes 0/1,461,894 · genomes 1/152,216 · joint denominator

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: IVD
Protein: p.Pro217fs
Coding: c.650del
MANE Select: NM_002225
dbSNP: rs1364046355
Type: Deletion
Location: chr15:40411653 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.25 · 5 PDB

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

Disease context

isovaleric acidemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Isovaleric acidemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

IVD c.1066del Likely pathogenic ★★ same condition
IVD c.685_687+15del Likely pathogenic ★★ same condition
IVD p.Ala128fs Pathogenic/Likely pathogenic ★★ same condition
IVD p.Arg410fs Pathogenic/Likely pathogenic ★★ same condition
IVD p.Asp212fs Likely pathogenic ★★ same condition
IVD p.Cys133fs Pathogenic/Likely pathogenic ★★ same condition
IVD p.Glu166fs Pathogenic/Likely pathogenic ★★ same condition
IVD p.Glu310fs Likely pathogenic ★★ same condition

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/ivd-p-pro217fs (accessed [today's date]).

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