# NM_003215.3(TEC):c.392A>G (p.Gln131Arg)

https://sugi.bio/variant/tec-p-gln131arg

## Summary

**TEC p.Gln131Arg (c.392A>G)** is classified **Uncertain significance** in TEC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely benign (0.1064); Ultra-rare (popmax 0.0506%, mid).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0506%, mid)

## 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 1 submitter.

*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.Gln131Arg |
| Coding change (HGVS c.) | c.392A>G |
| MANE Select transcript | [NM_003215](https://www.ncbi.nlm.nih.gov/nuccore/NM_003215) |
| Variant type | single nucleotide variant |
| Location | chr4:48170310-48170310 (GRCh38) |
| ClinVar | [VCV4182094](https://www.ncbi.nlm.nih.gov/clinvar/variation/4182094/) |

**All HGVS expressions:** `NC_000004.11:g.48172327T>C`, `NC_000004.12:g.48170310T>C`, `NM_003215.3:c.392A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1064)
- REVEL 0.644 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -8.598 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- SpliceAI predicts **acceptor gain** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.842, GERP 1.61, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.7**. 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 0.95** across the covering region of the MANE Select transcript (48,149,623–48,228,565), spanning 78,942 bp. Chi-square p 0.38. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0506%** (mid) · FAF95 0.0138% · FAF99 0.00734% · 3/5,924 in the highest group · 63/1,561,000 alleles overall — ultra-rare (popmax 0.0506%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0506% | 1,975 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0102% | 9,759 |
| Remaining individuals (not grpmax-eligible) | 0.0099% | 10,106 |
| Admixed American | 0.00669% | 14,953 |
| European (non-Finnish) | 0.00388% | 25,761 |
| African / African-American | 0.0027% | 36,989 |
| South Asian | 0.00113% | 88,726 |

*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}


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.


### 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 2025-08-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-02 |

**Reported phenotype names (ClinVar):** not specified, 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.Ala500Val](/variant/tec-p-ala500val), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 4182094). 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.*