Is IVD p.Arg78Pro (c.233G>C) pathogenic?

IVD p.Arg78Pro (c.233G>C) is classified Uncertain significance in IVD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-12). AlphaMissense: ambiguous (0.37); Very rare (popmax 0.00195%, nfe); Associated with Inborn genetic diseases.

What condition is associated with IVD p.Arg78Pro (c.233G>C)?

IVD p.Arg78Pro (c.233G>C) is associated with Inborn genetic diseases, isovaleric acidemia (ClinVar).

How common is IVD p.Arg78Pro (c.233G>C) in the general population?

IVD p.Arg78Pro (c.233G>C) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about IVD p.Arg78Pro (c.233G>C)?

AlphaMissense predicts ambiguous (score 0.37) — an in-silico prediction, not a clinical call.

IVD p.Arg78Pro

c.233G>C · rs771929559 · VCV459927

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.37 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.37	ambiguous
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -10.46	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R81P vs ClinVar R78P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00195% European (non-Finnish) · 23/1,179,816 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00143% 23/1,613,764 alleles · very rare exomes 22/1,461,564 · genomes 1/152,200 · 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.Arg78Pro
Coding: c.233G>C
MANE Select: NM_002225
dbSNP: rs771929559
Type: single nucleotide variant
Location: chr15:40407724 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.25 · 5 PDB
Residue 81 UniProt numbering: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isovaleric acidemia

Similar variants

IVD p.Arg78Ter Pathogenic ★★ 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-arg78pro (accessed [today's date]).

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