# NM_006372.5(SYNCRIP):c.894del (p.Ala299fs)

https://sugi.bio/variant/syncrip-p-ala299fs

## Summary

**SYNCRIP p.Ala299fs (c.894del)** is classified **Uncertain significance** in SYNCRIP (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-29). Associated with SYNCRIP-related disorder.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the SYNCRIP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to SYNCRIP-related disorder.

*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 | [SYNCRIP](https://sugi.bio/atlas/gene/SYNCRIP/) |
| Protein change (HGVS p.) | p.Ala299fs |
| Coding change (HGVS c.) | c.894del |
| MANE Select transcript | [NM_006372](https://www.ncbi.nlm.nih.gov/nuccore/NM_006372) |
| Variant type | Deletion |
| Location | chr6:85622596-85622596 (GRCh38) |
| ClinVar | [VCV4854056](https://www.ncbi.nlm.nih.gov/clinvar/variation/4854056/) |

**All HGVS expressions:** `NC_000006.11:g.86332314del`, `NC_000006.12:g.85622596del`, `NG_031848.1:g.25730del`, `NM_001159673.2:c.600del`, `NM_001159674.2:c.894del`, `NM_001159675.2:c.894del`, `NM_001159676.2:c.894del`, `NM_001159677.2:c.894del`, `NM_001253771.2:c.438del`, `NM_001410938.1:c.600del`, `NM_001439158.1:c.894del`, `NM_001439159.1:c.600del`, `NM_001439160.1:c.894del`, `NM_001439161.1:c.894del`, `NM_001439162.1:c.894del`, `NM_006372.5:c.894del`

## 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 7.692, GERP 2.21, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.249, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 11**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**SYNCRIP** population constraint: LOEUF 0.249, pLI 1, missense-Z 4.8524; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **SYNCRIP-related neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **299** lies in the rrm 2 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 70.83, 40% of residues very-high.

**4 experimental structure(s)** (PDB): [2DGU](https://www.rcsb.org/structure/2DGU), [2MXT](https://www.rcsb.org/structure/2MXT), [2NBB](https://www.rcsb.org/structure/2NBB), [6KOR](https://www.rcsb.org/structure/6KOR).

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

*Describes the biological roles of SYNCRIP (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:** SYNCRIP's established molecular role includes RNA binding. p.Ala299fs falls in the rrm 2 domain.


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

**Molecular function:** RNA binding.

**Biological process:** osteoblast differentiation, mRNA modification, negative regulation of translation, CRD-mediated mRNA stabilization, cellular response to type II interferon, negative regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-29.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-29 |

## Associated conditions {#conditions}

[SYNCRIP-related disorder](https://sugi.bio/atlas/disease/syncrip-related-disorder/).

**Reported phenotype names (ClinVar):** SYNCRIP-related disorder, SYNCRIP-related condition.

## Similar variants {#similar}

Related SYNCRIP variant pages (same residue, condition, or type): [SYNCRIP p.Pro147fs](/variant/syncrip-p-pro147fs), [SYNCRIP p.Ala521Thr](/variant/syncrip-p-ala521thr), [SYNCRIP p.Trp622Arg](/variant/syncrip-p-trp622arg), [SYNCRIP p.Val561Gly](/variant/syncrip-p-val561gly), [SYNCRIP p.Thr101Ile](/variant/syncrip-p-thr101ile), [SYNCRIP p.Tyr523His](/variant/syncrip-p-tyr523his), [SYNCRIP p.Arg548=](/variant/syncrip-p-arg548), [SYNCRIP p.Gln592=](/variant/syncrip-p-gln592).

### 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 4854056). 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.*