Is IVD p.Pro304= (c.912C>T) pathogenic?

IVD p.Pro304= (c.912C>T) is classified Likely benign in IVD (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-03). Very rare (popmax 0.00167%, amr); Associated with isovaleric acidemia.

What condition is associated with IVD p.Pro304= (c.912C>T)?

IVD p.Pro304= (c.912C>T) is associated with isovaleric acidemia (ClinVar).

How common is IVD p.Pro304= (c.912C>T) in the general population?

IVD p.Pro304= (c.912C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Isovaleric acidemia inherited?

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

IVD p.Pro304=

c.912C>T · rs1324916195 · VCV1154864

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

isovaleric acidemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.675	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.54, phastCons 1
Overall
CADD	10.92	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,032 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,614,212 alleles · very rare exomes 7/1,461,872 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,032
European (non-Finnish)	0.000508%	196,672

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.Pro304=
Coding: c.912C>T
MANE Select: NM_002225
dbSNP: rs1324916195
Type: single nucleotide variant
Location: chr15:40415434 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.25 · 5 PDB
Residue 304: an α-helix

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.144+1G>A Likely pathogenic ★★ same condition
IVD c.144+1G>C Pathogenic ★★ same condition
IVD c.286+2T>C Pathogenic/Likely pathogenic ★★ same condition
IVD c.286+5G>T Likely pathogenic ★★ same condition
IVD c.287-1G>A Pathogenic/Likely pathogenic ★★ same condition
IVD c.287-2A>G Pathogenic/Likely pathogenic ★★ same condition
IVD c.456+2T>C Pathogenic ★★ same condition
IVD c.457-2A>G 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-pro304 (accessed [today's date]).

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