Is UROD p.Ala246= (c.738C>T) pathogenic?

UROD p.Ala246= (c.738C>T) is classified Conflicting classifications of pathogenicity in UROD (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-16). Very rare (popmax 0.00534%, afr); Associated with familial porphyria cutanea tarda.

What condition is associated with UROD p.Ala246= (c.738C>T)?

UROD p.Ala246= (c.738C>T) is associated with familial porphyria cutanea tarda (ClinVar).

How common is UROD p.Ala246= (c.738C>T) in the general population?

UROD p.Ala246= (c.738C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

How is Porphyria cutanea tarda inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

UROD p.Ala246=

c.738C>T · rs757178659 · VCV297462

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

familial porphyria cutanea tarda

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 -7	GERP -3.2
Overall
CADD	1.232	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,916 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000558% 9/1,614,070 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,729
Admixed American	0.005%	19,999
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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: UROD
Protein: p.Ala246=
Coding: c.738C>T
MANE Select: NM_000374
dbSNP: rs757178659
Type: single nucleotide variant
Location: chr1:45014540 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 96.90 · 19 PDB
Residue 246: an α-helix

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

Disease context

familial porphyria cutanea tarda — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Porphyria cutanea tarda (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

UROD c.636+1G>C Pathogenic ★★ same condition
UROD p.Arg142Ter Pathogenic/Likely pathogenic ★★ same condition
UROD p.Arg193Pro Likely pathogenic ★★ same condition
UROD p.Gln116Ter Pathogenic ★★ same condition
UROD p.Gln206Ter Pathogenic/Likely pathogenic ★★ same condition
UROD p.Glu314= Pathogenic/Likely pathogenic ★★ same condition
UROD p.Gly281Val Pathogenic/Likely pathogenic ★★ same condition
UROD p.Met165Arg Pathogenic/Likely pathogenic ★★ 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/urod-p-ala246 (accessed [today's date]).

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