Is IVD p.Met1Val (c.1A>G) pathogenic?

IVD p.Met1Val (c.1A>G) is classified Likely pathogenic in IVD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-16). AlphaMissense: likely benign (0.1314); Absent from gnomAD v4.1; Associated with isovaleric acidemia.

What condition is associated with IVD p.Met1Val (c.1A>G)?

IVD p.Met1Val (c.1A>G) is associated with isovaleric acidemia (ClinVar).

How common is IVD p.Met1Val (c.1A>G) in the general population?

IVD p.Met1Val (c.1A>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.Met1Val (c.1A>G)?

AlphaMissense predicts likely benign (score 0.1314) — an in-silico prediction, not a clinical call.

IVD p.Met1Val

c.1A>G · VCV3577092

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1314 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

isovaleric acidemia

Computational evidence

Protein change
AlphaMissense	0.1314	likely benign ⚠ discordant with ClinVar
Consequence	start-loss	predicted loss-of-function
REVEL	0.588	indeterminate
SaProt	LLR -7.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 2.3, phastCons 1
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals. Predicted loss-of-function is descriptive, not an applied PVS1 code.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM M4V vs ClinVar M1V) — 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.Met1Val
Coding: c.1A>G
MANE Select: NM_002225
Type: single nucleotide variant
Location: chr15:40405828 (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.Met1Thr Uncertain significance ★ ⚠ same residue
IVD p.Met1Leu Likely 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
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-met1val (accessed [today's date]).

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