Is ALAD p.Asp88= (c.264C>T) pathogenic?

ALAD p.Asp88= (c.264C>T) is classified Conflicting classifications of pathogenicity in ALAD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-02-09). Ultra-rare (popmax 0.014%, nfe); Associated with porphyria due to ALA dehydratase deficiency.

What condition is associated with ALAD p.Asp88= (c.264C>T)?

ALAD p.Asp88= (c.264C>T) is associated with porphyria due to ALA dehydratase deficiency (ClinVar).

How common is ALAD p.Asp88= (c.264C>T) in the general population?

ALAD p.Asp88= (c.264C>T) is ultra-rare (popmax 0.014%, nfe) (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.Asp88=

c.264C>T · rs377534006 · VCV364652

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, nfe)

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	<0.2	all four deltas below 0.2 · G>T here scores Δ0.52 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.28	GERP -3.8, phastCons 0.001
Overall
CADD	3.688	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.014% European (non-Finnish) · 165/1,180,030 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0112% 180/1,613,980 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.014%	7,152
Admixed American	0.0117%	8,573
African / African-American	0.00667%	14,987
Remaining individualsnot grpmax-eligible	0.0048%	20,829

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.Asp88=
Coding: c.264C>T
MANE Select: NM_000031
dbSNP: rs377534006
Type: single nucleotide variant
Location: chr9:113390931 (GRCh38)
Gene constraint: LOEUF 0.63 · pLI 0.10 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.34 · 4 PDB
Residue 88: a β-strand

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-asp88 (accessed [today's date]).

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