Is UBTF p.Lys616Arg (c.1847A>G) pathogenic?

UBTF p.Lys616Arg (c.1847A>G) is classified Uncertain significance in UBTF (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-15). AlphaMissense: likely benign (0.1341); Very rare (popmax 0.00167%, amr); Associated with childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder.

How common is UBTF p.Lys616Arg (c.1847A>G) in the general population?

UBTF p.Lys616Arg (c.1847A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about UBTF p.Lys616Arg (c.1847A>G)?

AlphaMissense predicts likely benign (score 0.1341) — an in-silico prediction, not a clinical call.

UBTF p.Lys616Arg

Q: What condition is associated with UBTF p.Lys616Arg (c.1847A>G)?

UBTF p.Lys616Arg (c.1847A>G) is associated with childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder (ClinVar).

Q: How is Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder inherited?

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

c.1847A>G · VCV4883323

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1341 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder

Computational evidence

Protein change
AlphaMissense	0.1341	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -7.73	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 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.36	unconstrained · MANE · 2,513 bp · p 1.9e-20 · regional, not allelic
Overall
CADD	29.2	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 0.00167% Admixed American · 1/60,026 alleles

Overall 0.000657% 1/152,310 alleles · very rare

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: UBTF
Protein: p.Lys616Arg
Coding: c.1847A>G
MANE Select: NM_014233
Type: single nucleotide variant
Location: chr17:44209410 (GRCh38)
Gene constraint: LOEUF 0.133 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 4 PDB
Residue 616: a DNA-binding region

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

Disease context

childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

UBTF p.Asp262fs Uncertain significance ★ same condition
UBTF p.Asp681del Uncertain significance ★ same condition
UBTF c.59-143C>T Benign ★★ same type
UBTF p.Arg218Gln Uncertain significance ★ ⚠ same type
UBTF p.Asp738Asn Uncertain significance ★ ⚠ same type
UBTF p.Gly479Ser Uncertain significance ★ ⚠ same type
UBTF p.Met27Ile Uncertain significance ★ ⚠ same type
UBTF p.Asp696= Likely benign ★ 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/ubtf-p-lys616arg (accessed [today's date]).

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