Is IVD p.Ser407= (c.1221C>T) pathogenic?

IVD p.Ser407= (c.1221C>T) is classified Likely benign in IVD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-01). Very rare (popmax 0.00133%, afr); Associated with isovaleric acidemia.

What condition is associated with IVD p.Ser407= (c.1221C>T)?

IVD p.Ser407= (c.1221C>T) is associated with isovaleric acidemia (ClinVar).

How common is IVD p.Ser407= (c.1221C>T) in the general population?

IVD p.Ser407= (c.1221C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Isovaleric acidemia inherited?

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

IVD p.Ser407=

c.1221C>T · rs928740639 · VCV2191365

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

isovaleric acidemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6.2	GERP -2.9
Overall
CADD	4.515	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,922 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,076 alleles · very rare exomes 1/1,461,880 · genomes 2/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,922
European (non-Finnish)	0.000169%	590,023

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.Ser407=
Coding: c.1221C>T
MANE Select: NM_002225
dbSNP: rs928740639
Type: single nucleotide variant
Location: chr15:40418212 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.25 · 5 PDB
Residue 407: a binding site; a β-strand

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 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
IVD c.456+2T>C Pathogenic ★★ same condition
IVD c.457-2A>G 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-ser407 (accessed [today's date]).

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