# NM_001242818.2(DEF8):c.864G>C (p.Arg288Ser)

https://sugi.bio/variant/def8-p-arg288ser

## Summary

**DEF8 p.Arg288Ser (c.864G>C)** is classified **Uncertain significance** in DEF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: ambiguous (0.451); Very rare (popmax 0.005%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the DEF8 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 | [DEF8](https://sugi.bio/atlas/gene/DEF8/) |
| Protein change (HGVS p.) | p.Arg288Ser |
| Coding change (HGVS c.) | c.864G>C |
| MANE Select transcript | [NM_001242818](https://www.ncbi.nlm.nih.gov/nuccore/NM_001242818) |
| Variant type | single nucleotide variant |
| Location | chr16:89962068-89962068 (GRCh38) |
| ClinVar | [VCV3500762](https://www.ncbi.nlm.nih.gov/clinvar/variation/3500762/) |

**All HGVS expressions:** `NC_000016.10:g.89962068G>C`, `NC_000016.9:g.90028476G>C`, `NM_001242816.2:c.834G>C`, `NM_001242817.2:c.684G>C`, `NM_001242818.2:c.864G>C`, `NM_001242819.2:c.864G>C`, `NM_001242820.2:c.864G>C`, `NM_207514.3:c.1047G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.451) — no call either way
- REVEL 0.086 (moderately benign-leaning)
- SaProt LLR -5.539 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.41) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.208, GERP -3.1, phastCons 0.038 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R349S** vs ClinVar **R288S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 16.73**. 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 0.91** across the covering region of the MANE Select transcript (89,954,253–89,965,960), spanning 11,707 bp. Chi-square p 0.019. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.41**, donor loss **0.00**, acceptor gain **0.09**, donor gain **0.00**. Largest is acceptor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.09**, 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.*
- Population frequency (gnomAD v4.1): grpmax **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/60,010 in the highest group · 18/1,613,994 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.005% | 20,003 |
| European (non-Finnish) | 0.00127% | 78,668 |

*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}

**DEF8** population constraint: LOEUF 0.928, pLI 1.1796e-09, missense-Z 0.56367. *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 76.04, 54% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-10.

**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 | 2024-11-10 |

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

## Similar variants {#similar}

Related DEF8 variant pages (same residue, condition, or type): [DEF8 p.Gln29Glu](/variant/def8-p-gln29glu), [DEF8 p.Glu122=](/variant/def8-p-glu122), [DEF8 p.Pro318=](/variant/def8-p-pro318), [DEF8 p.Val356Met](/variant/def8-p-val356met), [DEF8 c.-11+101C>T](/variant/def8-c-minus-11-plus-101c-t), [DEF8 c.-11+104C>T](/variant/def8-c-minus-11-plus-104c-t), [DEF8 c.-11+10G>T](/variant/def8-c-minus-11-plus-10g-t), [DEF8 c.-11+113C>A](/variant/def8-c-minus-11-plus-113c-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3500762). 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.*