Is IVD p.Arg78Ter (c.232C>T) pathogenic?

IVD p.Arg78Ter (c.232C>T) is classified Pathogenic in IVD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-06-27). Very rare (popmax 0.00333%, amr); Associated with isovaleric acidemia.

What condition is associated with IVD p.Arg78Ter (c.232C>T)?

IVD p.Arg78Ter (c.232C>T) is associated with isovaleric acidemia (ClinVar).

How common is IVD p.Arg78Ter (c.232C>T) in the general population?

IVD p.Arg78Ter (c.232C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

How is Isovaleric acidemia inherited?

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

IVD p.Arg78Ter

c.232C>T · rs765815516 · VCV370807

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

isovaleric acidemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 12
Splicing
SpliceAI	Δ0.97	donor gain · deltas
Pangolin	Δ0.83	gain · loss 0.78 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.3	GERP -0.49, phastCons 0.62
Overall
CADD	51.0	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 0.00333% Admixed American · 2/60,006 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.0018% 29/1,613,712 alleles · very rare exomes 27/1,461,520 · genomes 2/152,192 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,003
European (non-Finnish)	0.00203%	49,156
Remaining individualsnot grpmax-eligible	0.0016%	62,468
African / African-American	0.00133%	74,912
South Asian	0.0011%	91,066

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.Arg78Ter
Coding: c.232C>T
MANE Select: NM_002225
dbSNP: rs765815516
Type: single nucleotide variant
Location: chr15:40407723 (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 p.Arg78Pro Uncertain significance ★★ ⚠ same residue
IVD p.Arg78= Likely benign ★ same residue
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

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-arg78ter (accessed [today's date]).

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