# NM_014844.5(TECPR2):c.3849G>A (p.Val1283=)

https://sugi.bio/variant/tecpr2-p-val1283

## Summary

**TECPR2 p.Val1283= (c.3849G>A)** is classified **Likely benign** in TECPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-14). Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 49.

**At a glance:** Likely benign · review: Single submitter · rsID rs1182508451 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TECPR2 gene that is classified as likely benign — not considered 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.Val1283= |
| Coding change (HGVS c.) | c.3849G>A |
| MANE Select transcript | [NM_014844](https://www.ncbi.nlm.nih.gov/nuccore/NM_014844) |
| dbSNP | [rs1182508451](https://www.ncbi.nlm.nih.gov/snp/rs1182508451/) |
| Variant type | single nucleotide variant |
| Location | chr14:102497038-102497038 (GRCh38) |
| ClinVar | [VCV2747458](https://www.ncbi.nlm.nih.gov/clinvar/variation/2747458/) |

**All HGVS expressions:** `NC_000014.8:g.102963375G>A`, `NC_000014.9:g.102497038G>A`, `NG_042851.1:g.139127G>A`, `NM_014844.5:c.3849G>A`

## 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 -6.741, GERP -3.55 — fast-evolving / accelerated position
- CADD: **PHRED 0.11**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.46 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- 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.*

## 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}


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

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-14.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-14 |

## 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, NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IX, WITH DEVELOPMENTAL DELAY, Spastic paraplegia 49, autosomal recessive.

## Similar variants {#similar}

Related TECPR2 variant pages (same residue, condition, or type): [TECPR2 c.1084+2T>C](/variant/tecpr2-c-1084-plus-2t-c), [TECPR2 c.1418-2A>G](/variant/tecpr2-c-1418-minus-2a-g), [TECPR2 c.2753-1G>A](/variant/tecpr2-c-2753-minus-1g-a), [TECPR2 p.Gln1189Ter](/variant/tecpr2-p-gln1189ter), [TECPR2 p.Gln191Ter](/variant/tecpr2-p-gln191ter), [TECPR2 p.Gln852Ter](/variant/tecpr2-p-gln852ter), [TECPR2 p.Trp1024Ter](/variant/tecpr2-p-trp1024ter), [TECPR2 p.Trp1288Ter](/variant/tecpr2-p-trp1288ter).

### 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 2747458). 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.*