# NM_006372.5(SYNCRIP):c.980A>T (p.Glu327Val)

https://sugi.bio/variant/syncrip-p-glu327val

## Summary

**SYNCRIP p.Glu327Val (c.980A>T)** is classified **Uncertain significance** in SYNCRIP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). AlphaMissense: likely pathogenic (0.8769); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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.

*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.Glu327Val |
| Coding change (HGVS c.) | c.980A>T |
| MANE Select transcript | [NM_006372](https://www.ncbi.nlm.nih.gov/nuccore/NM_006372) |
| Variant type | single nucleotide variant |
| Location | chr6:85622510-85622510 (GRCh38) |
| ClinVar | [VCV4681065](https://www.ncbi.nlm.nih.gov/clinvar/variation/4681065/) |

**All HGVS expressions:** `NC_000006.11:g.86332228T>A`, `NC_000006.12:g.85622510T>A`, `NG_031848.1:g.25816A>T`, `NM_001159673.2:c.686A>T`, `NM_001159674.2:c.903+77A>T`, `NM_001159675.2:c.903+77A>T`, `NM_001159676.2:c.980A>T`, `NM_001159677.2:c.980A>T`, `NM_001253771.2:c.524A>T`, `NM_001410938.1:c.686A>T`, `NM_001439158.1:c.980A>T`, `NM_001439159.1:c.686A>T`, `NM_001439160.1:c.980A>T`, `NM_001439161.1:c.980A>T`, `NM_001439162.1:c.980A>T`, `NM_006372.5:c.980A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8769)
- REVEL 0.252 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -10.682 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- SpliceAI predicts **donor loss** (Δ 0.56) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.915, GERP 1.89, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.8**. 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 0.34** across the covering region of the MANE Select transcript (85,618,825–85,622,593), spanning 3,768 bp — the region is depleted of missense variation. Chi-square p 3.9e-16. 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 **0.56**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 28 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.35** (loss), gain 0.01 / loss 0.35. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **327** lies in a turn.

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.


### 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 2025-07-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-02 |

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

## Similar variants {#similar}

Related SYNCRIP variant pages (same residue, condition, or type): [SYNCRIP p.Ala216Thr](/variant/syncrip-p-ala216thr), [SYNCRIP p.Asn243Ser](/variant/syncrip-p-asn243ser), [SYNCRIP p.Pro440Leu](/variant/syncrip-p-pro440leu), [SYNCRIP p.Pro508Leu](/variant/syncrip-p-pro508leu), [SYNCRIP p.Ser116Gly](/variant/syncrip-p-ser116gly), [SYNCRIP p.Glu612Val](/variant/syncrip-p-glu612val), [SYNCRIP p.Arg446Ter](/variant/syncrip-p-arg446ter), [SYNCRIP c.803-3C>A](/variant/syncrip-c-803-minus-3c-a).

### 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 4681065). 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.*