# NM_001014989.2(LAT):c.39C>T (p.Pro13=)

https://sugi.bio/variant/lat-p-pro13

## Summary

**LAT p.Pro13= (c.39C>T)** is classified **Likely benign** in LAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-18). Very rare (popmax 0.00596%, sas).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs749827158 · 2 submitters · very rare (popmax 0.00596%, sas)

## For patients & families {#patients}

This is a change in the LAT gene that is classified as likely benign — not considered disease-causing, 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 | [LAT](https://sugi.bio/atlas/gene/LAT/) |
| Protein change (HGVS p.) | p.Pro13= |
| Coding change (HGVS c.) | c.39C>T |
| MANE Select transcript | [NM_001014987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001014987) (variant reported on NM_001014989) |
| dbSNP | [rs749827158](https://www.ncbi.nlm.nih.gov/snp/rs749827158/) |
| Variant type | single nucleotide variant |
| Location | chr16:28984900-28984900 (GRCh38) |
| ClinVar | [VCV2646359](https://www.ncbi.nlm.nih.gov/clinvar/variation/2646359/) |

**All HGVS expressions:** `NC_000016.10:g.28984900C>T`, `NC_000016.9:g.28996221C>T`, `NG_193172.1:g.188C>T`, `NM_001014989.2:c.39C>T`

## 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 -2.239 — fast-evolving / accelerated position
- CADD: **PHRED 3.993**. 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** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00596%** (sas) · FAF95 0.00234% · FAF99 0.00146% · 5/83,924 in the highest group · 34/1,548,330 alleles overall — very rare (popmax 0.00596%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.015% | 6,666 |
| South Asian (grpmax) | 0.00596% | 16,785 |
| East Asian | 0.00245% | 40,888 |
| Admixed American | 0.00197% | 50,812 |
| Finnish (not grpmax-eligible) | 0.00173% | 57,912 |
| European (non-Finnish) | 0.0014% | 71,648 |
| African / African-American | 0.00137% | 73,006 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}


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.


### 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 2024-11-18.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-18 |

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

## Similar variants {#similar}

Related LAT variant pages (same residue, condition, or type): [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), [LAT p.Asp126Val](/variant/lat-p-asp126val).

### 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 2646359). 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.*