# NM_014844.5(TECPR2):c.326C>G (p.Ser109Ter)

https://sugi.bio/variant/tecpr2-p-ser109ter

## Summary

**TECPR2 p.Ser109Ter (c.326C>G)** is classified **Likely pathogenic** in TECPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). Very rare (popmax 0.00134%, afr); Associated with hereditary spastic paraplegia 49.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00134%, afr)

## 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.Ser109Ter |
| Coding change (HGVS c.) | c.326C>G |
| MANE Select transcript | [NM_014844](https://www.ncbi.nlm.nih.gov/nuccore/NM_014844) |
| Variant type | single nucleotide variant |
| Location | chr14:102407444-102407444 (GRCh38) |
| ClinVar | [VCV4815749](https://www.ncbi.nlm.nih.gov/clinvar/variation/4815749/) |

**All HGVS expressions:** `NC_000014.8:g.102873781C>G`, `NC_000014.9:g.102407444C>G`, `NG_042851.1:g.49533C>G`, `NM_001172631.3:c.326C>G`, `NM_014844.5:c.326C>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 5.782, GERP 0.937, phastCons 0.99 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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 3 of 20**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 35.0**. 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.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00134%** (afr) · 1/74,902 in the highest group · 1/1,613,082 alleles overall — very rare (popmax 0.00134%, afr).

*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 pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-04.

**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 | 2025-08-04 |

## 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.Ser109=](/variant/tecpr2-p-ser109), [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).

### 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 4815749). 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.*