Is UTP4 p.Pro282= (c.846G>A) pathogenic?

UTP4 p.Pro282= (c.846G>A) is classified Conflicting classifications of pathogenicity in UTP4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-10). Very rare (popmax 0.00263%, nfe); Associated with hereditary North American Indian childhood cirrhosis.

What condition is associated with UTP4 p.Pro282= (c.846G>A)?

UTP4 p.Pro282= (c.846G>A) is associated with hereditary North American Indian childhood cirrhosis (ClinVar).

How common is UTP4 p.Pro282= (c.846G>A) in the general population?

UTP4 p.Pro282= (c.846G>A) is very rare (popmax 0.00263%, nfe) (gnomAD).

How is Progressive familial intrahepatic cholestasis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

UTP4 p.Pro282=

c.846G>A · rs150182351 · VCV888314

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 0.00263%, nfe)

Conditions

hereditary North American Indian childhood cirrhosis

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 -3.9	GERP -5.1
Overall
CADD	3.378	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00263% European (non-Finnish) · 31/1,180,034 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.0154% 248/1,614,214 alleles · very rare exomes 212/1,461,884 · genomes 36/152,330 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.632%	158
Remaining individualsnot grpmax-eligible	0.0416%	2,404
European (non-Finnish)grpmax	0.00263%	38,066
East Asian	0.00223%	44,884
South Asian	0.0022%	45,543
African / African-American	0.00133%	75,062

Ashkenazi Jewish 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: UTP4
Protein: p.Pro282=
Coding: c.846G>A
MANE Select: NM_032830
dbSNP: rs150182351
Type: single nucleotide variant
Location: chr16:69150644 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.28 · 3 PDB
Residue 282: a β-strand

Full UTP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary North American Indian childhood cirrhosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Progressive familial intrahepatic cholestasis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy, Neonatal

Similar variants

UTP4 c.1287+6T>C Uncertain significance ★★ same condition
UTP4 c.1444+6A>C Uncertain significance ★★ same condition
UTP4 p.Arg291His Uncertain significance ★★ ⚠ same condition
UTP4 p.Arg417Trp Uncertain significance ★★ ⚠ same condition
UTP4 p.Asn537Ser Uncertain significance ★★ ⚠ same condition
UTP4 p.Gly459Glu Uncertain significance ★★ ⚠ same condition
UTP4 c.1164+8A>G Benign/Likely benign ★★ same condition
UTP4 c.1287+4A>G Benign/Likely benign ★★ 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/utp4-p-pro282 (accessed [today's date]).

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