Is UTP4 p.Phe436= (c.1308C>T) pathogenic?

UTP4 p.Phe436= (c.1308C>T) is classified Conflicting classifications of pathogenicity in UTP4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-28). Ultra-rare (popmax 0.0683%, amr); Associated with hereditary North American Indian childhood cirrhosis.

What condition is associated with UTP4 p.Phe436= (c.1308C>T)?

UTP4 p.Phe436= (c.1308C>T) is associated with hereditary North American Indian childhood cirrhosis (ClinVar).

How common is UTP4 p.Phe436= (c.1308C>T) in the general population?

UTP4 p.Phe436= (c.1308C>T) is ultra-rare (popmax 0.0683%, amr) (gnomAD).

How is Progressive familial intrahepatic cholestasis inherited?

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

UTP4 p.Phe436=

c.1308C>T · rs140221825 · VCV885213

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0683%, amr)

Conditions

hereditary North American Indian childhood cirrhosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 2.8	GERP 2, phastCons 1
Overall
CADD	12.67	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0683% Admixed American · 41/60,022 alleles

Filtering AF 0.0517% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0459%

Overall 0.0338% 546/1,614,234 alleles · ultra-rare exomes 507/1,461,886 · genomes 39/152,348 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0683%	1,464
European (non-Finnish)	0.0407%	2,458
Remaining individualsnot grpmax-eligible	0.0288%	3,473
African / African-American	0.00933%	10,723

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.Phe436=
Coding: c.1308C>T
MANE Select: NM_032830
dbSNP: rs140221825
Type: single nucleotide variant
Location: chr16:69157104 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.28 · 3 PDB
Residue 436: an α-helix

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-phe436 (accessed [today's date]).

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