# NM_016038.4(SBDS):c.528C>T (p.Phe176=)

https://sugi.bio/variant/sbds-p-phe176

## Summary

**SBDS p.Phe176= (c.528C>T)** is classified **Uncertain significance** in SBDS (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-30). Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the SBDS 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 | [SBDS](https://sugi.bio/atlas/gene/SBDS/) |
| Protein change (HGVS p.) | p.Phe176= |
| Coding change (HGVS c.) | c.528C>T |
| MANE Select transcript | [NM_016038](https://www.ncbi.nlm.nih.gov/nuccore/NM_016038) |
| Variant type | single nucleotide variant |
| Location | chr7:66991233-66991233 (GRCh38) |
| ClinVar | [VCV4896138](https://www.ncbi.nlm.nih.gov/clinvar/variation/4896138/) |

**All HGVS expressions:** `LRG_104:g.9369C>T`, `LRG_104t1:c.528C>T`, `NC_000007.13:g.66456220G>A`, `NC_000007.14:g.66991233G>A`, `NG_007277.1:g.9369C>T`, `NM_016038.4:c.528C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.41) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.87, GERP 0.837, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.83**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.41**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.41**, donor gain **0.00**.
- Pangolin: Δ**0.34** (gain), gain 0.34 / loss 0.00. 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 (gnomAD v4.1): grpmax **0.0165%** (mid) · 1/6,062 in the highest group · 1/1,613,966 alleles overall — ultra-rare (popmax 0.0165%, mid).

*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}

**SBDS** population constraint: LOEUF 1.08, pLI 1.3519e-05, missense-Z 1.4414. *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):

- **Shwachman-Diamond syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **176** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 73.97, 4% of residues very-high.

**6 experimental structure(s)** (PDB): [2KDO](https://www.rcsb.org/structure/2KDO), [2L9N](https://www.rcsb.org/structure/2L9N), [5AN9](https://www.rcsb.org/structure/5AN9), [5ANB](https://www.rcsb.org/structure/5ANB), [5ANC](https://www.rcsb.org/structure/5ANC), [6QKL](https://www.rcsb.org/structure/6QKL).

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

*Describes the biological roles of SBDS (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:** SBDS's established molecular role includes RNA binding.


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

**Molecular function:** RNA binding, microtubule binding, rRNA binding, ribosome binding.

**Biological process:** hematopoietic progenitor cell differentiation, rRNA processing, mitotic spindle organization, bone mineralization, leukocyte chemotaxis, cytosolic ribosome assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-07-30.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-07-30 |

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

## Similar variants {#similar}

Related SBDS variant pages (same residue, condition, or type): [SBDS c.258+1G>C](/variant/sbds-c-258-plus-1g-c), [SBDS c.258+2T>C](/variant/sbds-c-258-plus-2t-c), [SBDS c.624+1G>A](/variant/sbds-c-624-plus-1g-a), [SBDS p.Arg218Gln](/variant/sbds-p-arg218gln), [SBDS p.Arg218Ter](/variant/sbds-p-arg218ter), [SBDS p.Lys33Thr](/variant/sbds-p-lys33thr), [SBDS p.Ser55Ter](/variant/sbds-p-ser55ter), [SBDS p.Tyr32Cys](/variant/sbds-p-tyr32cys).

### 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 4896138). 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.*