# NM_015908.6(SRRT):c.1352C>T (p.Ala451Val)

https://sugi.bio/variant/srrt-p-ala451val

## Summary

**SRRT p.Ala451Val (c.1352C>T)** is classified **Uncertain significance** in SRRT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-05). AlphaMissense: likely pathogenic (0.9674); Very rare (popmax 0.00237%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs888110002 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00237%, nfe)

## For patients & families {#patients}

This is a change in the SRRT 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 | [SRRT](https://sugi.bio/atlas/gene/SRRT/) |
| Protein change (HGVS p.) | p.Ala451Val |
| Coding change (HGVS c.) | c.1352C>T |
| MANE Select transcript | [NM_015908](https://www.ncbi.nlm.nih.gov/nuccore/NM_015908) |
| dbSNP | [rs888110002](https://www.ncbi.nlm.nih.gov/snp/rs888110002/) |
| Variant type | single nucleotide variant |
| Location | chr7:100885735-100885735 (GRCh38) |
| ClinVar | [VCV3170241](https://www.ncbi.nlm.nih.gov/clinvar/variation/3170241/) |

**All HGVS expressions:** `NC_000007.13:g.100483356C>T`, `NC_000007.14:g.100885735C>T`, `NG_111935.1:g.32C>T`, `NM_001128852.2:c.1349C>T`, `NM_001128853.2:c.1352C>T`, `NM_001128854.2:c.1349C>T`, `NM_015908.6:c.1352C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9674)
- REVEL 0.154 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -9.709 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 7.665, GERP 1.52, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.3**. 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 0.78** across the covering region of the MANE Select transcript (100,885,218–100,887,466), spanning 2,248 bp. Chi-square p 3.6e-06. 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 (C>G, Δ0.20 donor loss), 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 **0.00237%** (nfe) · FAF95 0.00165% · FAF99 0.00142% · 28/1,179,806 in the highest group · 31/1,613,548 alleles overall — very rare (popmax 0.00237%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00237% | 42,136 |
| South Asian | 0.0022% | 45,518 |
| African / African-American | 0.00134% | 74,870 |

*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}

**SRRT** population constraint: LOEUF 0.404, pLI 1, missense-Z 2.7639. *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 **451** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 66.61, 29% of residues very-high.

**6 experimental structure(s)** (PDB): [5OO6](https://www.rcsb.org/structure/5OO6), [6F7J](https://www.rcsb.org/structure/6F7J), [6F7P](https://www.rcsb.org/structure/6F7P), [6F7S](https://www.rcsb.org/structure/6F7S), [6F8D](https://www.rcsb.org/structure/6F8D), [8PMP](https://www.rcsb.org/structure/8PMP).

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

*Describes the biological roles of SRRT (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:** SRRT's established molecular role includes RNA binding. In Reactome, SRRT is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** SRRT loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

SRRT participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| [Nuclear RNA decay](https://reactome.org/content/detail/R-HSA-9930044) | curated |
| [RNA polymerase II transcribes snRNA genes](https://reactome.org/content/detail/R-HSA-6807505) | curated |
| [mRNA Polyadenylation](https://reactome.org/content/detail/R-HSA-9770562) | curated |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | curated |

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

**Molecular function:** RNA binding, protein-macromolecule adaptor activity, mRNA cap binding complex binding.

**Biological process:** primary miRNA processing.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-05.

**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 | 2023-12-05 |

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

## Similar variants {#similar}

Related SRRT variant pages (same residue, condition, or type): [SRRT c.1042-18C>G](/variant/srrt-c-1042-minus-18c-g), [SRRT c.1042-7C>T](/variant/srrt-c-1042-minus-7c-t), [SRRT c.2556-9A>T](/variant/srrt-c-2556-minus-9a-t), [SRRT p.Arg518=](/variant/srrt-p-arg518), [SRRT p.Glu205=](/variant/srrt-p-glu205), [SRRT p.Leu157=](/variant/srrt-p-leu157), [SRRT p.Leu265=](/variant/srrt-p-leu265), [SRRT p.Ala190Val](/variant/srrt-p-ala190val).

### 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 3170241). 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.*