Is DDC p.Arg27His (c.80G>A) pathogenic?

DDC p.Arg27His (c.80G>A) is classified Uncertain significance in DDC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-03). AlphaMissense: likely benign (0.2028); Very rare (popmax 0.00891%, eas); Associated with aromatic L-amino acid decarboxylase deficiency.

What condition is associated with DDC p.Arg27His (c.80G>A)?

DDC p.Arg27His (c.80G>A) is associated with aromatic L-amino acid decarboxylase deficiency (ClinVar).

How common is DDC p.Arg27His (c.80G>A) in the general population?

DDC p.Arg27His (c.80G>A) is very rare (popmax 0.00891%, 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.

What do computational predictors say about DDC p.Arg27His (c.80G>A)?

AlphaMissense predicts likely benign (score 0.2028) — an in-silico prediction, not a clinical call.

DDC p.Arg27His

c.80G>A · rs781573378 · VCV1445291

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2028 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

aromatic L-amino acid decarboxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.2028	likely benign
REVEL	0.434	indeterminate
SaProt	LLR -7.20	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 3.8	GERP 2.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 81 kb · p 0.058 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,878 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000867% 14/1,614,172 alleles · very rare exomes 14/1,461,854 · genomes 0/152,318 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,220
Finnishnot grpmax-eligible	0.00781%	12,808
Admixed American	0.00167%	60,028
African / African-American	0.00133%	75,032
European (non-Finnish)	0.000254%	393,338

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.Arg27His
Coding: c.80G>A
MANE Select: NM_001082971
dbSNP: rs781573378
Type: single nucleotide variant
Location: chr7:50544006 (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

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.Arg27Cys Uncertain significance ★ ⚠ 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
DDC p.Arg160Trp 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-arg27his (accessed [today's date]).

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