Is ALAD p.Leu226= (c.678G>T) pathogenic?

ALAD p.Leu226= (c.678G>T) is classified Conflicting classifications of pathogenicity in ALAD (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2020-05-20). Rare (popmax 0.278%, eas); Associated with porphyria due to ALA dehydratase deficiency.

What condition is associated with ALAD p.Leu226= (c.678G>T)?

ALAD p.Leu226= (c.678G>T) is associated with porphyria due to ALA dehydratase deficiency (ClinVar).

How common is ALAD p.Leu226= (c.678G>T) in the general population?

ALAD p.Leu226= (c.678G>T) is rare (popmax 0.278%, eas) (gnomAD).

How is Porphyria due to ALA dehydratase deficiency inherited?

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

ALAD p.Leu226=

c.678G>T · rs190497588 · VCV364645

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.278%, eas)

Conditions

porphyria due to ALA dehydratase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.32, phastCons 1
Overall
CADD	8.927	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.278% East Asian · 125/44,886 alleles

Filtering AF 0.239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.224%

Overall 0.00855% 138/1,614,190 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.278%	359
Remaining individualsnot grpmax-eligible	0.0176%	5,683
Admixed American	0.00167%	60,028
South Asian	0.0011%	91,090

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: ALAD
Protein: p.Leu226=
Coding: c.678G>T
MANE Select: NM_000031
dbSNP: rs190497588
Type: single nucleotide variant
Location: chr9:113389635 (GRCh38)
Gene constraint: LOEUF 0.63 · pLI 0.10 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.34 · 4 PDB

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

Disease context

porphyria due to ALA dehydratase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Porphyria due to ALA dehydratase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

ALAD p.Gly133Arg Likely pathogenic ★★ same condition
ALAD c.*127C>T Uncertain significance ★★ same condition
ALAD c.*363G>A Uncertain significance ★★ same condition
ALAD p.Ala93Thr Uncertain significance ★★ ⚠ same condition
ALAD p.Arg147Cys Uncertain significance ★★ ⚠ same condition
ALAD p.Arg174His Uncertain significance ★★ ⚠ same condition
ALAD p.Arg262Trp Uncertain significance ★★ ⚠ same condition
ALAD p.Asp239Asn Uncertain significance ★★ ⚠ 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/alad-p-leu226 (accessed [today's date]).

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