# NM_014844.5(TECPR2):c.1274del (p.Pro425fs)

https://sugi.bio/variant/tecpr2-p-pro425fs

## Summary

**TECPR2 p.Pro425fs (c.1274del)** is classified **Likely pathogenic** in TECPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-30). Associated with hereditary spastic paraplegia 49.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the TECPR2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to hereditary spastic paraplegia 49.

*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 recessive |
| Age of onset (of this condition) | Infancy |
| Diagnostic panels | TECPR2 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Hereditary sensory and autonomic neuropathy due to TECPR2 mutation** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Recurrent respiratory infections — Very frequent (99-80%)
- Brachycephaly — Frequent (79-30%)
- Microcephaly — Frequent (79-30%)
- Full cheeks — Frequent (79-30%)
- Low anterior hairline — Frequent (79-30%)
- Round face — Frequent (79-30%)
- Hypomimic face — Frequent (79-30%)
- Short neck — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013568/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TECPR2](https://sugi.bio/atlas/gene/TECPR2/) |
| Protein change (HGVS p.) | p.Pro425fs |
| Coding change (HGVS c.) | c.1274del |
| MANE Select transcript | [NM_014844](https://www.ncbi.nlm.nih.gov/nuccore/NM_014844) |
| Variant type | Deletion |
| Location | chr14:102431981-102431981 (GRCh38) |
| ClinVar | [VCV4815738](https://www.ncbi.nlm.nih.gov/clinvar/variation/4815738/) |

**All HGVS expressions:** `NC_000014.8:g.102898322del`, `NC_000014.9:g.102431985del`, `NG_042851.1:g.74074del`, `NM_001172631.3:c.1274del`, `NM_014844.5:c.1274del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.382, GERP -0.948, phastCons 0.417 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.607, pLI 2.1398e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 20**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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.*

## Gene constraint & dosage {#gene-context}

**TECPR2** population constraint: LOEUF 0.607, pLI 2.1398e-07, missense-Z 2.3384; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **425** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 68.27, 38% of residues very-high.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-30.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-09-30 |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 49](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-49/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 49, TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability, Spastic paraplegia 49, autosomal recessive, NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IX, WITH DEVELOPMENTAL DELAY.

## Similar variants {#similar}

Related TECPR2 variant pages (same residue, condition, or type): [TECPR2 p.Pro425=](/variant/tecpr2-p-pro425), [TECPR2 c.222delG](/variant/tecpr2-c-222delg), [TECPR2 p.Asn1277fs](/variant/tecpr2-p-asn1277fs), [TECPR2 p.Asn944fs](/variant/tecpr2-p-asn944fs), [TECPR2 p.Asp259fs](/variant/tecpr2-p-asp259fs), [TECPR2 p.Gln1263fs](/variant/tecpr2-p-gln1263fs), [TECPR2 p.Gly584fs](/variant/tecpr2-p-gly584fs), [TECPR2 p.Leu1139fs](/variant/tecpr2-p-leu1139fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4815738). 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.*