# NM_014844.5(TECPR2):c.999G>A (p.Ser333=)

https://sugi.bio/variant/tecpr2-p-ser333

## Summary

**TECPR2 p.Ser333= (c.999G>A)** is classified **Likely benign** in TECPR2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-11). Very rare (popmax 0.00717%, afr); Associated with hereditary spastic paraplegia 49.

**At a glance:** Likely benign · review: Single submitter · rsID rs369972265 · 2 submitters · 1 linked condition · very rare (popmax 0.00717%, afr)

## For patients & families {#patients}

This is a change in the TECPR2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, 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.Ser333= |
| Coding change (HGVS c.) | c.999G>A |
| MANE Select transcript | [NM_014844](https://www.ncbi.nlm.nih.gov/nuccore/NM_014844) |
| dbSNP | [rs369972265](https://www.ncbi.nlm.nih.gov/snp/rs369972265/) |
| Variant type | single nucleotide variant |
| Location | chr14:102428297-102428297 (GRCh38) |
| ClinVar | [VCV696381](https://www.ncbi.nlm.nih.gov/clinvar/variation/696381/) |

**All HGVS expressions:** `NC_000014.8:g.102894634G>A`, `NC_000014.9:g.102428297G>A`, `NG_042851.1:g.70386G>A`, `NM_001172631.3:c.999G>A`, `NM_014844.5:c.999G>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 0.599, GERP -1.42, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 12.79**. 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, Δ0.22 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 (gnomAD v4.1): grpmax **0.00717%** (afr) · FAF95 0.00361% · FAF99 0.00324% · 5/69,780 in the highest group · 62/1,587,698 alleles overall — very rare (popmax 0.00717%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00717% | 13,956 |
| European (non-Finnish) | 0.00461% | 21,671 |
| East Asian | 0.00229% | 43,684 |
| Admixed American | 0.00176% | 56,788 |
| Remaining individuals (not grpmax-eligible) | 0.00163% | 61,350 |

*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 2025-12-11.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-04-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-11 |

## 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 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 696381). 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.*