Is ALAD p.Pro321Ser (c.961C>T) pathogenic?

ALAD p.Pro321Ser (c.961C>T) is classified Uncertain significance in ALAD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: ambiguous (0.3985); Ultra-rare (popmax 0.0156%, eas); Associated with Inborn genetic diseases.

What condition is associated with ALAD p.Pro321Ser (c.961C>T)?

ALAD p.Pro321Ser (c.961C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ALAD p.Pro321Ser (c.961C>T) in the general population?

ALAD p.Pro321Ser (c.961C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about ALAD p.Pro321Ser (c.961C>T)?

AlphaMissense predicts ambiguous (score 0.3985) — an in-silico prediction, not a clinical call.

ALAD p.Pro321Ser

c.961C>T · rs762227805 · VCV2602023

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3985 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3985	ambiguous
REVEL	0.657	pathogenic-leaning
SaProt	LLR -11.21	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 5,256 bp · p 6.2e-09 · regional, not allelic
Overall
CADD	28.0	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 0.0156% East Asian · 7/44,898 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.000558% 9/1,614,012 alleles · ultra-rare exomes 8/1,461,840 · genomes 1/152,172 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,414
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	8.47e-05%	1,180,044

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.Pro321Ser
Coding: c.961C>T
MANE Select: NM_000031
dbSNP: rs762227805
Type: single nucleotide variant
Location: chr9:113388332 (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 321: 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.Pro321= Likely benign ★ 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-pro321ser (accessed [today's date]).

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