Is IVD p.Pro291Ala (c.871C>G) pathogenic?

IVD p.Pro291Ala (c.871C>G) is classified Uncertain significance in IVD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-10). AlphaMissense: ambiguous (0.3662); Absent from gnomAD v4.1; Associated with isovaleric acidemia.

What condition is associated with IVD p.Pro291Ala (c.871C>G)?

IVD p.Pro291Ala (c.871C>G) is associated with isovaleric acidemia (ClinVar).

How common is IVD p.Pro291Ala (c.871C>G) in the general population?

IVD p.Pro291Ala (c.871C>G) is absent from gnomAD v4.1 (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.Pro291Ala (c.871C>G)?

AlphaMissense predicts ambiguous (score 0.3662) — an in-silico prediction, not a clinical call.

IVD p.Pro291Ala

c.871C>G · VCV3678130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3662 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

isovaleric acidemia

Computational evidence

Protein change
AlphaMissense	0.3662	ambiguous
REVEL	0.811	moderately pathogenic-leaning
SaProt	LLR -14.29	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	28.0	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 P294A vs ClinVar P291A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IVD
Protein: p.Pro291Ala
Coding: c.871C>G
MANE Select: NM_002225
Type: single nucleotide variant
Location: chr15:40414975 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.25 · 5 PDB
Residue 294 UniProt numbering: 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.Pro291Leu Likely pathogenic ★ same residue
IVD p.Pro291= Likely benign ★ same residue
IVD p.Pro291fs Pathogenic ★★ 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

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-pro291ala (accessed [today's date]).

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