Is DDC p.Ala45Thr (c.133G>A) pathogenic?

DDC p.Ala45Thr (c.133G>A) is classified Conflicting classifications of pathogenicity in DDC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-08). AlphaMissense: likely benign (0.0631); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with DDC p.Ala45Thr (c.133G>A)?

DDC p.Ala45Thr (c.133G>A) is associated with Inborn genetic diseases, aromatic L-amino acid decarboxylase deficiency (ClinVar).

How common is DDC p.Ala45Thr (c.133G>A) in the general population?

DDC p.Ala45Thr (c.133G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about DDC p.Ala45Thr (c.133G>A)?

AlphaMissense predicts likely benign (score 0.0631) — an in-silico prediction, not a clinical call.

DDC p.Ala45Thr

c.133G>A · rs755313812 · VCV2189367

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0631 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0631	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -5.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.5	GERP -5.3
Regional constraint	o/e 0.92	unconstrained · MANE · 81 kb · p 0.058 · regional, not allelic
Overall
CADD	0.007	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000867% 14/1,614,032 alleles · ultra-rare exomes 12/1,461,880 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00134%	74,898
South Asian	0.0011%	91,084
European (non-Finnish)	0.000678%	147,504

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.Ala45Thr
Coding: c.133G>A
MANE Select: NM_001082971
dbSNP: rs755313812
Type: single nucleotide variant
Location: chr7:50543953 (GRCh38)
Gene constraint: LOEUF 0.922 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.88 · 8 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: aromatic L-amino acid decarboxylase deficiency

Similar variants

DDC p.Ala45Val Uncertain significance ★★ ⚠ same residue
DDC p.Ala45= Conflicting classifications of pathogenicity ★ same residue
DDC c.1041+1G>A Pathogenic/Likely pathogenic ★★ same condition
DDC c.201+1G>C Likely pathogenic ★★ same condition
DDC c.201+5G>C Pathogenic/Likely pathogenic ★★ same condition
DDC c.714+4A>T Pathogenic ★★ same condition
DDC p.Ala275Thr Pathogenic/Likely pathogenic ★★ same condition
DDC p.Ala91Val 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/ddc-p-ala45thr (accessed [today's date]).

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