# NM_080823.4(SRMS):c.1145C>T (p.Pro382Leu)

https://sugi.bio/variant/srms-p-pro382leu

## Summary

**SRMS p.Pro382Leu (c.1145C>T)** is classified **Uncertain significance** in SRMS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-09). AlphaMissense: likely benign (0.1184); Rare (popmax 0.135%, sas).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs374780062 · 2 submitters · AlphaMissense likely benign · rare (popmax 0.135%, sas)

## For patients & families {#patients}

This is a change in the SRMS 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 | [SRMS](https://sugi.bio/atlas/gene/SRMS/) |
| Protein change (HGVS p.) | p.Pro382Leu |
| Coding change (HGVS c.) | c.1145C>T |
| MANE Select transcript | [NM_080823](https://www.ncbi.nlm.nih.gov/nuccore/NM_080823) |
| dbSNP | [rs374780062](https://www.ncbi.nlm.nih.gov/snp/rs374780062/) |
| Variant type | single nucleotide variant |
| Location | chr20:63541331-63541331 (GRCh38) |
| ClinVar | [VCV994223](https://www.ncbi.nlm.nih.gov/clinvar/variation/994223/) |

**All HGVS expressions:** `NC_000020.10:g.62172684G>A`, `NC_000020.11:g.63541331G>A`, `NM_080823.2:c.1145C>T`, `NM_080823.4:c.1145C>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** (0.1184)
- REVEL 0.34 (indeterminate)
- SaProt LLR -8.076 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 3.018, GERP -0.988, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.39**. 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 1.03** across the covering region of the MANE Select transcript (63,540,821–63,547,463), spanning 6,642 bp. Chi-square p 0.4. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.27 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 **0.135%** (sas) · FAF95 0.115% · FAF99 0.107% · 109/80,474 in the highest group · 259/1,542,054 alleles overall — rare (popmax 0.135%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.135% | 738 |
| Middle Eastern | 0.0872% | 1,146 |
| African / African-American | 0.0799% | 1,251 |
| Remaining individuals (not grpmax-eligible) | 0.0253% | 3,959 |
| Admixed American | 0.00619% | 16,146 |
| European (non-Finnish) | 0.00584% | 17,112 |
| East Asian | 0.00452% | 22,129 |

*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}

**SRMS** population constraint: LOEUF 1.445, pLI 2.8232e-16, missense-Z -1.3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **382** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 83.99, 53% of residues very-high.

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

*Describes the biological roles of SRMS (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:** SRMS's established molecular role includes protein tyrosine kinase activity. p.Pro382Leu falls in the protein kinase domain.


### Pathways affected {#pathways}

SRMS participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [PTK6 Down-Regulation](https://reactome.org/content/detail/R-HSA-8849472) | curated |

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

**Molecular function:** protein tyrosine kinase activity.

**Biological process:** peptidyl-tyrosine phosphorylation, peptidyl-tyrosine autophosphorylation, positive regulation of TORC1 signaling.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-09.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-06-19 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-09 |

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

## Similar variants {#similar}

Related SRMS variant pages (same residue, condition, or type): [SRMS p.Pro188=](/variant/srms-p-pro188), [SRMS p.Ala162Pro](/variant/srms-p-ala162pro), [SRMS p.Ala175Val](/variant/srms-p-ala175val), [SRMS p.Ala199Thr](/variant/srms-p-ala199thr), [SRMS p.Ala449Gly](/variant/srms-p-ala449gly), [SRMS p.Ala453Val](/variant/srms-p-ala453val), [SRMS p.Ala46Thr](/variant/srms-p-ala46thr), [SRMS p.Ala58Val](/variant/srms-p-ala58val).

### 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 994223). 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.*