Is ALAD p.Phe12= (c.36C>T) pathogenic?

ALAD p.Phe12= (c.36C>T) is classified Likely benign in ALAD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-07). Ultra-rare (popmax 0.017%, mid).

How common is ALAD p.Phe12= (c.36C>T) in the general population?

ALAD p.Phe12= (c.36C>T) is ultra-rare (popmax 0.017%, mid) (gnomAD).

ALAD p.Phe12=

c.36C>T · rs121912984 · VCV2041998

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 0.99, phastCons 1
Overall
CADD	11.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.017% Middle Eastern · 1/5,874 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00041% 6/1,461,640 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.017%	5,874
South Asian	0.00329%	30,355
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	8.47e-05%	1,180,038

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.Phe12=
Coding: c.36C>T
MANE Select: NM_000031
dbSNP: rs121912984
Type: single nucleotide variant
Location: chr9:113393524 (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 12: a UniProt-annotated variant site (in an asymptomatic patient with alad deficiency; also found in a hereditary coproporphyria patient carrying the r-279 mutation in cpox; hexamer with almost no residual activity); a β-strand

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

Similar variants

ALAD p.Phe12Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ALAD p.Gly133Arg Likely pathogenic ★★ same type
ALAD c.*127C>T Uncertain significance ★★ same type
ALAD c.*363G>A Uncertain significance ★★ same type
ALAD p.Ala93Thr Uncertain significance ★★ ⚠ same type
ALAD p.Arg147Cys Uncertain significance ★★ ⚠ same type
ALAD p.Arg174His Uncertain significance ★★ ⚠ same type
ALAD p.Arg17Gln Uncertain significance ★★ ⚠ same type

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-phe12 (accessed [today's date]).

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