Is ALAD p.Arg240Gln (c.719G>A) pathogenic?

ALAD p.Arg240Gln (c.719G>A) is classified Uncertain significance in ALAD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: ambiguous (0.4951); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with ALAD p.Arg240Gln (c.719G>A)?

ALAD p.Arg240Gln (c.719G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ALAD p.Arg240Gln (c.719G>A) in the general population?

ALAD p.Arg240Gln (c.719G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ALAD p.Arg240Gln (c.719G>A)?

AlphaMissense predicts ambiguous (score 0.4951) — an in-silico prediction, not a clinical call.

ALAD p.Arg240Gln

c.719G>A · VCV4267937

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4951	ambiguous
REVEL	0.698	pathogenic-leaning
SaProt	LLR -10.46	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.7	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	34.0	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 0.00223% East Asian · 1/44,888 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00186% 30/1,614,020 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,828
East Asiangrpmax	0.00223%	44,888
European (non-Finnish)	0.00212%	47,201
African / African-American	0.00133%	74,928

Remaining individuals 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.Arg240Gln
Coding: c.719G>A
MANE Select: NM_000031
Type: single nucleotide variant
Location: chr9:113389520 (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 240: a UniProt-annotated variant site (in ahepp; mixture of about 80% hexamer and 20% octamer; about 4% residual activity); an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALAD p.Arg240Pro Uncertain significance ★ ⚠ same residue
ALAD p.Arg240Trp Uncertain significance ★ ⚠ same residue
ALAD p.Arg17Gln Uncertain significance ★★ ⚠ same condition
ALAD p.Arg222Cys Uncertain significance ★★ ⚠ same condition
ALAD p.Arg90Gln Uncertain significance ★★ ⚠ same condition
ALAD p.Asp239Asn Uncertain significance ★★ ⚠ same condition
ALAD p.Gln45His 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-arg240gln (accessed [today's date]).

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