Is ALAD p.Arg231Gln (c.692G>A) pathogenic?

ALAD p.Arg231Gln (c.692G>A) is classified Likely benign in ALAD (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). AlphaMissense: likely benign (0.1724); Rare (popmax 0.105%, eas); Associated with porphyria due to ALA dehydratase deficiency.

What condition is associated with ALAD p.Arg231Gln (c.692G>A)?

ALAD p.Arg231Gln (c.692G>A) is associated with porphyria due to ALA dehydratase deficiency (ClinVar).

How common is ALAD p.Arg231Gln (c.692G>A) in the general population?

ALAD p.Arg231Gln (c.692G>A) is rare (popmax 0.105%, 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.Arg231Gln (c.692G>A)?

AlphaMissense predicts likely benign (score 0.1724) — an in-silico prediction, not a clinical call.

ALAD p.Arg231Gln

c.692G>A · rs201420740 · VCV915072

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1724 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

porphyria due to ALA dehydratase deficiency

Computational evidence

Protein change
AlphaMissense	0.1724	likely benign
REVEL	0.649	pathogenic-leaning
SaProt	LLR -12.83	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, 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 0.105% East Asian · 47/44,886 alleles

Filtering AF 0.0808% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0725%

Overall 0.00458% 74/1,614,186 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.105%	955
South Asian	0.022%	4,554
Remaining individualsnot grpmax-eligible	0.0032%	31,253
African / African-American	0.00266%	37,536
European (non-Finnish)	0.000254%	393,345

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.Arg231Gln
Coding: c.692G>A
MANE Select: NM_000031
dbSNP: rs201420740
Type: single nucleotide variant
Location: chr9:113389621 (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 231: 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.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-arg231gln (accessed [today's date]).

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