Is DDC p.Ile433fs (c.1297dup) pathogenic?

DDC p.Ile433fs (c.1297dup) is classified Pathogenic in DDC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-26). Very rare (popmax 0.00445%, eas); Associated with aromatic L-amino acid decarboxylase deficiency.

What condition is associated with DDC p.Ile433fs (c.1297dup)?

DDC p.Ile433fs (c.1297dup) is associated with aromatic L-amino acid decarboxylase deficiency (ClinVar).

How common is DDC p.Ile433fs (c.1297dup) in the general population?

DDC p.Ile433fs (c.1297dup) is very rare (popmax 0.00445%, eas) (gnomAD).

How is Aromatic L-amino acid decarboxylase deficiency inherited?

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

DDC p.Ile433fs

c.1297dup · rs760629324 · VCV1068763

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Conditions

aromatic L-amino acid decarboxylase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,894 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000372% 6/1,614,036 alleles · very rare exomes 4/1,461,882 · genomes 2/152,154 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,447
European (non-Finnish)	0.000339%	295,006

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: DDC
Protein: p.Ile433fs
Coding: c.1297dup
MANE Select: NM_001082971
dbSNP: rs760629324
Type: Duplication
Location: chr7:50463376 (GRCh38)
Gene constraint: LOEUF 0.922 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.88 · 8 PDB
Residue 433: a β-strand

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

Disease context

aromatic L-amino acid decarboxylase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Aromatic L-amino acid decarboxylase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DDC p.Ser416fs Pathogenic/Likely pathogenic ★★ same condition
DDC p.Asp339fs Pathogenic ★ same condition
DDC p.Gln190fs Pathogenic ★ same condition
DDC p.Thr454fs Likely pathogenic ★ same condition
DDC p.Ala91_Leu94dup Uncertain significance ★ same condition
DDC p.Ile433Val Uncertain significance ★ ⚠ same residue
DDC c.1141-18dup Benign ★ same condition
DDC c.570+18dup Benign ★ 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/ddc-p-ile433fs (accessed [today's date]).

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