# NM_001014987.2(LAT):c.249A>G (p.Arg83=)

https://sugi.bio/variant/lat-p-arg83

## Summary

**LAT p.Arg83= (c.249A>G)** is classified **Likely benign** in LAT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-29). Very rare (popmax 0.00102%, nfe).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs761916378 · 3 submitters · very rare (popmax 0.00102%, nfe)

## For patients & families {#patients}

This is a change in the LAT gene that is classified as likely benign — not considered disease-causing, submitted by 3 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 | [LAT](https://sugi.bio/atlas/gene/LAT/) |
| Protein change (HGVS p.) | p.Arg83= |
| Coding change (HGVS c.) | c.249A>G |
| MANE Select transcript | [NM_001014987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001014987) |
| dbSNP | [rs761916378](https://www.ncbi.nlm.nih.gov/snp/rs761916378/) |
| Variant type | single nucleotide variant |
| Location | chr16:28986385-28986385 (GRCh38) |
| ClinVar | [VCV1929867](https://www.ncbi.nlm.nih.gov/clinvar/variation/1929867/) |

**All HGVS expressions:** `NC_000016.10:g.28986385A>G`, `NC_000016.9:g.28997706A>G`, `NM_001014987.2:c.249A>G`, `NM_001014988.2:c.246A>G`, `NM_001014989.1:c.357A>G`, `NM_001014989.2:c.357A>G`, `NM_014387.4:c.249A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.30) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.516, phastCons 0.929 — weakly conserved position
- CADD: **PHRED 8.565**. 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 deltas (raw): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**. Largest is acceptor loss, 30 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.04**, 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00102%** (nfe) · FAF95 0.000542% · FAF99 0.000428% · 12/1,179,986 in the highest group · 12/1,613,510 alleles overall — very rare (popmax 0.00102%, nfe).

*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}

**LAT** population constraint: LOEUF 0.474, pLI 0.99364, missense-Z 1.3219. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **severe combined immunodeficiency due to LAT deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **83** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 59.77, 5% of residues very-high.

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

*Describes the biological roles of LAT (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:** LAT's established molecular role includes protein kinase binding. p.Arg83= falls in the disordered region.


### Pathways affected {#pathways}

LAT participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [GPVI-mediated activation cascade](https://reactome.org/content/detail/R-HSA-114604) | curated |
| [Generation of second messenger molecules](https://reactome.org/content/detail/R-HSA-202433) | curated |
| [DAP12 signaling](https://reactome.org/content/detail/R-HSA-2424491) | other |
| [FCERI mediated Ca+2 mobilization](https://reactome.org/content/detail/R-HSA-2871809) | other |
| [FCERI mediated MAPK activation](https://reactome.org/content/detail/R-HSA-2871796) | other |
| [Fc epsilon receptor (FCERI) signaling](https://reactome.org/content/detail/R-HSA-2454202) | other |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | other |

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

**Molecular function:** protein kinase binding, signaling receptor complex adaptor activity, signaling adaptor activity, molecular condensate scaffold activity.

**Biological process:** immune response, integrin-mediated signaling pathway, Ras protein signal transduction, calcium-mediated signaling, membrane raft distribution, intracellular signal transduction.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-29.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-12-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-29 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-06 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related LAT variant pages (same residue, condition, or type): [LAT p.Arg83Gly](/variant/lat-p-arg83gly), [LAT c.-41G>T](/variant/lat-c-minus-41g-t), [LAT p.Ala183Val](/variant/lat-p-ala183val), [LAT p.Arg53Gln](/variant/lat-p-arg53gln), [LAT p.Arg93Gln](/variant/lat-p-arg93gln), [LAT p.Arg93Trp](/variant/lat-p-arg93trp), [LAT p.Arg98Gln](/variant/lat-p-arg98gln), [LAT p.Arg98Trp](/variant/lat-p-arg98trp).

### 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 1929867). 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.*