# NM_014233.4(UBTF):c.403C>T (p.Pro135Ser)

https://sugi.bio/variant/ubtf-p-pro135ser

## Summary

**UBTF p.Pro135Ser (c.403C>T)** is classified **Uncertain significance** in UBTF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-15). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2144550110 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the UBTF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Childhood |

**Commonly reported features of Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Atypical behavior — Very frequent (99-80%)
- Dysarthria — Very frequent (99-80%)
- Dysphagia — Very frequent (99-80%)
- Cerebral atrophy — Very frequent (99-80%)
- Abnormality of extrapyramidal motor function — Very frequent (99-80%)
- Developmental regression — Very frequent (99-80%)
- Abnormal pyramidal sign — Very frequent (99-80%)
- Hyperintensity of cerebral white matter on MRI — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013658/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [UBTF](https://sugi.bio/atlas/gene/UBTF/) |
| Protein change (HGVS p.) | p.Pro135Ser |
| Coding change (HGVS c.) | c.403C>T |
| MANE Select transcript | [NM_014233](https://www.ncbi.nlm.nih.gov/nuccore/NM_014233) |
| dbSNP | [rs2144550110](https://www.ncbi.nlm.nih.gov/snp/rs2144550110/) |
| Variant type | single nucleotide variant |
| Location | chr17:44215725-44215725 (GRCh38) |
| ClinVar | [VCV1330567](https://www.ncbi.nlm.nih.gov/clinvar/variation/1330567/) |

**All HGVS expressions:** `NC_000017.10:g.42293093G>A`, `NC_000017.11:g.44215725G>A`, `NG_029864.1:g.10902C>T`, `NM_001076683.2:c.403C>T`, `NM_001076684.3:c.403C>T`, `NM_014233.4:c.403C>T`, `NR_045058.2:n.574C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9992)
- REVEL 0.924 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.141 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.664, GERP 1.04, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.00** across the covering region of the MANE Select transcript (44,215,670–44,215,737), spanning 67 bp — the region is depleted of missense variation. Chi-square p 2.3e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-15 |

## Associated conditions {#conditions}

[childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder](https://sugi.bio/atlas/disease/childhood-onset-motor-and-cognitive-regression-syndrome-with-extrapyramidal-movement-disorder/).

**Reported phenotype names (ClinVar):** Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, NEURODEGENERATION, CHILDHOOD-ONSET, WITH BRAIN ATROPHY.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1330567). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*