Is ALAD p.Arg221Ser (c.661C>A) pathogenic?

ALAD p.Arg221Ser (c.661C>A) is classified Uncertain significance in ALAD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-21). AlphaMissense: likely pathogenic (0.9823); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ALAD p.Arg221Ser (c.661C>A)?

ALAD p.Arg221Ser (c.661C>A) is associated with Inborn genetic diseases (ClinVar).

How common is ALAD p.Arg221Ser (c.661C>A) in the general population?

ALAD p.Arg221Ser (c.661C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALAD p.Arg221Ser (c.661C>A)?

AlphaMissense predicts likely pathogenic (score 0.9823) — an in-silico prediction, not a clinical call.

ALAD p.Arg221Ser

c.661C>A · rs777855664 · VCV2337852

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9823 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9823	likely pathogenic · top 4% in ALAD
REVEL	0.875	moderately pathogenic-leaning
SaProt	LLR -11.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	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	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALAD
Protein: p.Arg221Ser
Coding: c.661C>A
MANE Select: NM_000031
dbSNP: rs777855664
Type: single nucleotide variant
Location: chr9:113389652 (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 221: a binding site

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.Arg221Cys 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
ALAD p.Met304Thr 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-arg221ser (accessed [today's date]).

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