Is UTP4 p.Asn537Ser (c.1610A>G) pathogenic?

UTP4 p.Asn537Ser (c.1610A>G) is classified Uncertain significance in UTP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-06-13). AlphaMissense: likely benign (0.0604); Ultra-rare (popmax 0.0121%, sas); Associated with UTP4-related disorder.

What condition is associated with UTP4 p.Asn537Ser (c.1610A>G)?

UTP4 p.Asn537Ser (c.1610A>G) is associated with UTP4-related disorder, hereditary North American Indian childhood cirrhosis (ClinVar).

How common is UTP4 p.Asn537Ser (c.1610A>G) in the general population?

UTP4 p.Asn537Ser (c.1610A>G) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about UTP4 p.Asn537Ser (c.1610A>G)?

AlphaMissense predicts likely benign (score 0.0604) — an in-silico prediction, not a clinical call.

UTP4 p.Asn537Ser

c.1610A>G · rs138922775 · VCV886106

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0604 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

UTP4-related disorder

Computational evidence

Protein change
AlphaMissense	0.0604	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -6.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.6	GERP -5.5
Regional constraint	o/e 0.95	unconstrained · MANE · 35 kb · p 0.18 · regional, not allelic
Overall
CADD	1.997	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% South Asian · 11/91,088 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00601% 97/1,614,146 alleles · ultra-rare exomes 93/1,461,854 · genomes 4/152,292 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,281
Remaining individualsnot grpmax-eligible	0.0112%	8,929
Admixed American	0.00833%	12,002
European (non-Finnish)	0.00602%	16,620
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Finnishnot grpmax-eligible	0.00156%	64,032
African / African-American	0.00133%	75,052

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.Asn537Ser
Coding: c.1610A>G
MANE Select: NM_032830
dbSNP: rs138922775
Type: single nucleotide variant
Location: chr16:69163141 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.28 · 3 PDB
Residue 537: a β-strand

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

Disease context

UTP4-related disorder

Also linked: hereditary North American Indian childhood cirrhosis

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.Gly459Glu Uncertain significance ★★ ⚠ same condition
UTP4 p.Val522Met 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-asn537ser (accessed [today's date]).

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