# NM_003215.3(TEC):c.1499C>T (p.Ala500Val)

https://sugi.bio/variant/tec-p-ala500val

## Summary

**TEC p.Ala500Val (c.1499C>T)** is classified **Uncertain significance** in TEC (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-20). AlphaMissense: likely benign (0.097); Very rare (popmax 0.00879%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs763650133 · 2 submitters · AlphaMissense likely benign · very rare (popmax 0.00879%, sas)

## For patients & families {#patients}

This is a change in the TEC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TEC](https://sugi.bio/atlas/gene/TEC/) |
| Protein change (HGVS p.) | p.Ala500Val |
| Coding change (HGVS c.) | c.1499C>T |
| MANE Select transcript | [NM_003215](https://www.ncbi.nlm.nih.gov/nuccore/NM_003215) |
| dbSNP | [rs763650133](https://www.ncbi.nlm.nih.gov/snp/rs763650133/) |
| Variant type | single nucleotide variant |
| Location | chr4:48141391-48141391 (GRCh38) |
| ClinVar | [VCV2214873](https://www.ncbi.nlm.nih.gov/clinvar/variation/2214873/) |

**All HGVS expressions:** `NC_000004.11:g.48143408G>A`, `NC_000004.12:g.48141391G>A`, `NM_003215.3:c.1499C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.097)
- REVEL 0.08 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.845 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.392, GERP -0.928, phastCons 0.046 — weakly conserved position
- CADD: **PHRED 19.76**. 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 0.74** across the covering region of the MANE Select transcript (48,137,419–48,149,622), spanning 12,203 bp. Chi-square p 3.1e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.19**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 36 bp away.
- SpliceAI deltas (masked): acceptor loss **0.19**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.29** (loss), gain 0.03 / loss 0.29. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00879%** (sas) · FAF95 0.00437% · FAF99 0.00312% · 8/91,054 in the highest group · 10/1,613,512 alleles overall — very rare (popmax 0.00879%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00879% | 11,382 |
| African / African-American | 0.00133% | 74,926 |
| European (non-Finnish) | 8.48e-05% | 1,179,857 |

*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}

**TEC** population constraint: LOEUF 0.89, pLI 2.2863e-14, missense-Z 2.0469. *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 **500** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 85.48, 56% of residues very-high.

**1 experimental structure(s)** (PDB): [2LUL](https://www.rcsb.org/structure/2LUL).

## What this gene does {#gene-function}

*Describes the biological roles of TEC (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TEC's established molecular role includes non-membrane spanning protein tyrosine kinase activity. p.Ala500Val falls in the protein kinase domain.


### Pathways affected {#pathways}

TEC participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interleukin-3, Interleukin-5 and GM-CSF signaling](https://reactome.org/content/detail/R-HSA-512988) | curated |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | curated |
| [FCERI mediated Ca+2 mobilization](https://reactome.org/content/detail/R-HSA-2871809) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** non-membrane spanning protein tyrosine kinase activity.

**Biological process:** integrin-mediated signaling pathway, regulation of platelet activation, B cell receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-20.

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

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-20 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

**Reported phenotype names (ClinVar):** not specified, Colon adenocarcinoma, AllHighlyPenetrant.

## Similar variants {#similar}

Related TEC variant pages (same residue, condition, or type): [TEC c.496-1G>A](/variant/tec-c-496-minus-1g-a), [TEC p.Arg202Ser](/variant/tec-p-arg202ser), [TEC p.Arg262Leu](/variant/tec-p-arg262leu), [TEC p.Arg29Gly](/variant/tec-p-arg29gly), [TEC p.Arg342Gln](/variant/tec-p-arg342gln), [TEC p.Arg390Gln](/variant/tec-p-arg390gln), [TEC p.Arg617Cys](/variant/tec-p-arg617cys), [TEC p.Asn112Ile](/variant/tec-p-asn112ile).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2214873). 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.*