Is IVD p.Arg50Pro (c.149G>C) pathogenic?

IVD p.Arg50Pro (c.149G>C) is classified Pathogenic/Likely pathogenic in IVD (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-07). AlphaMissense: likely pathogenic (0.986); Very rare (popmax 0.005%, amr); Associated with isovaleric acidemia.

What condition is associated with IVD p.Arg50Pro (c.149G>C)?

IVD p.Arg50Pro (c.149G>C) is associated with isovaleric acidemia (ClinVar).

How common is IVD p.Arg50Pro (c.149G>C) in the general population?

IVD p.Arg50Pro (c.149G>C) is very rare (popmax 0.005%, amr) (gnomAD).

How is Isovaleric acidemia inherited?

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

What do computational predictors say about IVD p.Arg50Pro (c.149G>C)?

AlphaMissense predicts likely pathogenic (score 0.986) — an in-silico prediction, not a clinical call.

IVD p.Arg50Pro

c.149G>C · rs2229311 · VCV188922

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isovaleric acidemia

Computational evidence

Protein change
AlphaMissense	0.986	likely pathogenic ✓ concordant with ClinVar · top 7% in IVD
REVEL	0.957	strongly pathogenic-leaning
SaProt	LLR -14.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	34.0	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 R53P vs ClinVar R50P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,000 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.0028% 41/1,461,676 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,000
European (non-Finnish)	0.00314%	31,888
South Asian	0.0011%	91,060

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.Arg50Pro
Coding: c.149G>C
MANE Select: NM_002225
dbSNP: rs2229311
Type: single nucleotide variant
Location: chr15:40407640 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.25 · 5 PDB
Residue 50: 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 p.Arg50Cys Pathogenic/Likely pathogenic ★★ same residue
IVD p.Arg50His Pathogenic/Likely pathogenic ★★ same residue
IVD p.Arg50Leu Likely pathogenic ★★ same residue
IVD p.Arg50= Conflicting classifications of pathogenicity ★ same residue
IVD p.Arg50Gly Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg50pro (accessed [today's date]).

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