# NM_007247.6(SYNRG):c.1217C>T (p.Pro406Leu)

https://sugi.bio/variant/synrg-p-pro406leu

## Summary

**SYNRG p.Pro406Leu (c.1217C>T)** is classified **Uncertain significance** in SYNRG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). AlphaMissense: likely benign (0.106); Very rare (popmax 0.000424%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the SYNRG 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 | [SYNRG](https://sugi.bio/atlas/gene/SYNRG/) |
| Protein change (HGVS p.) | p.Pro406Leu |
| Coding change (HGVS c.) | c.1217C>T |
| MANE Select transcript | [NM_007247](https://www.ncbi.nlm.nih.gov/nuccore/NM_007247) |
| Variant type | single nucleotide variant |
| Location | chr17:37570767-37570767 (GRCh38) |
| ClinVar | [VCV3964672](https://www.ncbi.nlm.nih.gov/clinvar/variation/3964672/) |

**All HGVS expressions:** `NC_000017.10:g.35930866G>A`, `NC_000017.11:g.37570767G>A`, `NM_001163544.3:c.983C>T`, `NM_001163545.3:c.980C>T`, `NM_001163546.3:c.983C>T`, `NM_001163547.3:c.864+1024C>T`, `NM_001405103.1:c.1520C>T`, `NM_007247.6:c.1217C>T`, `NM_080550.5:c.983C>T`, `NM_198882.3:c.983C>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** (0.106)
- REVEL 0.113 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.467 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.33) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.916, GERP 2.54, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.2**. 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 0.85** across the covering region of the MANE Select transcript (37,518,943–37,584,677), spanning 65,734 bp. Chi-square p 8.4e-08. 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 **0.33**, donor gain **0.07**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.33**, donor gain **0.07**.
- Population frequency (gnomAD v4.1): grpmax **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,180,044 in the highest group · 5/1,614,210 alleles overall — very rare (popmax 0.000424%, 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}

**SYNRG** population constraint: LOEUF 0.38, pLI 1, missense-Z 2.7005. *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 48.74, 10% of residues very-high.

**1 experimental structure(s)** (PDB): [2MX7](https://www.rcsb.org/structure/2MX7).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-30.

**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 | 2025-05-30 |

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

## Similar variants {#similar}

Related SYNRG variant pages (same residue, condition, or type): [SYNRG p.Pro406Thr](/variant/synrg-p-pro406thr), [SYNRG c.372-1G>A](/variant/synrg-c-372-minus-1g-a), [SYNRG c.3813+5G>A](/variant/synrg-c-3813-plus-5g-a), [SYNRG p.Ala1246Val](/variant/synrg-p-ala1246val), [SYNRG p.Ala1291Thr](/variant/synrg-p-ala1291thr), [SYNRG p.Ala15Thr](/variant/synrg-p-ala15thr), [SYNRG p.Ala171Val](/variant/synrg-p-ala171val), [SYNRG p.Ala17Val](/variant/synrg-p-ala17val).

### 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 3964672). 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.*