Is ALAD p.Arg262Trp (c.784C>T) pathogenic?

ALAD p.Arg262Trp (c.784C>T) is classified Uncertain significance in ALAD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-05-15). AlphaMissense: ambiguous (0.3861); Very rare (popmax 0.00446%, eas); Associated with porphyria due to ALA dehydratase deficiency.

What condition is associated with ALAD p.Arg262Trp (c.784C>T)?

ALAD p.Arg262Trp (c.784C>T) is associated with porphyria due to ALA dehydratase deficiency (ClinVar).

How common is ALAD p.Arg262Trp (c.784C>T) in the general population?

ALAD p.Arg262Trp (c.784C>T) is very rare (popmax 0.00446%, 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.

What do computational predictors say about ALAD p.Arg262Trp (c.784C>T)?

AlphaMissense predicts ambiguous (score 0.3861) — an in-silico prediction, not a clinical call.

ALAD p.Arg262Trp

c.784C>T · rs777485356 · VCV546208

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3861 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

porphyria due to ALA dehydratase deficiency

Computational evidence

Protein change
AlphaMissense	0.3861	ambiguous
REVEL	0.626	indeterminate
SaProt	LLR -14.96	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.3	GERP 0.9, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 5,256 bp · p 6.2e-09 · regional, not allelic
Overall
CADD	31.0	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 0.00446% East Asian · 2/44,882 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00118% 19/1,613,496 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,935
East Asiangrpmax	0.00446%	22,441
Remaining individualsnot grpmax-eligible	0.0016%	62,444
African / African-American	0.00134%	74,878
European (non-Finnish)	0.000763%	131,115

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg262Trp
Coding: c.784C>T
MANE Select: NM_000031
dbSNP: rs777485356
Type: single nucleotide variant
Location: chr9:113389455 (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 262: an α-helix

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.Asp239Asn Uncertain significance ★★ ⚠ same condition
ALAD p.Gly292Arg 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-arg262trp (accessed [today's date]).

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