# NM_005816.5(CD96):c.741C>T (p.Val247=)

https://sugi.bio/variant/cd96-p-val247

## Summary

**CD96 p.Val247= (c.741C>T)** is classified **Likely benign** in CD96 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-14). Very rare (popmax 0.005%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs879595027 · 1 submitter · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the CD96 gene that is classified as likely benign — not considered disease-causing, 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 | [CD96](https://sugi.bio/atlas/gene/CD96/) |
| Protein change (HGVS p.) | p.Val247= |
| Coding change (HGVS c.) | c.741C>T |
| MANE Select transcript | [NM_005816](https://www.ncbi.nlm.nih.gov/nuccore/NM_005816) |
| dbSNP | [rs879595027](https://www.ncbi.nlm.nih.gov/snp/rs879595027/) |
| Variant type | single nucleotide variant |
| Location | chr3:111579224-111579224 (GRCh38) |
| ClinVar | [VCV759165](https://www.ncbi.nlm.nih.gov/clinvar/variation/759165/) |

**All HGVS expressions:** `NC_000003.11:g.111298071C>T`, `NC_000003.12:g.111579224C>T`, `NG_012156.2:g.42146C>T`, `NM_001318889.2:c.741C>T`, `NM_005816.5:c.741C>T`, `NM_198196.3:c.789C>T`, `NR_134917.2:n.793C>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 **donor loss** (Δ 0.24) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.595, GERP -0.389, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 4.715**. 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 **0.24**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.24**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.29** (loss), gain 0.01 / loss 0.29. 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 **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/59,976 in the highest group · 9/1,586,954 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00974% | 10,266 |
| Admixed American (grpmax) | 0.005% | 19,992 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CD96** population constraint: LOEUF 1.16, pLI 0.00038083, missense-Z 0.11578. *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):

- **C syndrome** — Limited (AD)

## Protein context {#protein}

Residue **247** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 65.81, 19% of residues very-high.

**1 experimental structure(s)** (PDB): [6ARQ](https://www.rcsb.org/structure/6ARQ).

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

*Describes the biological roles of CD96 (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.*


### Pathways affected {#pathways}

CD96 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |

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

**Biological process:** cell-matrix adhesion.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-06-14.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-06-14 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related CD96 variant pages (same residue, condition, or type): [CD96 c.1249+1G>A](/variant/cd96-c-1249-plus-1g-a), [CD96 c.544-1512C>T](/variant/cd96-c-544-minus-1512c-t), [CD96 p.Asp205Gly](/variant/cd96-p-asp205gly), [CD96 p.Asp224Asn](/variant/cd96-p-asp224asn), [CD96 p.Ile151Thr](/variant/cd96-p-ile151thr), [CD96 p.Leu120Pro](/variant/cd96-p-leu120pro), [CD96 p.Lys500Arg](/variant/cd96-p-lys500arg), [CD96 p.Pro346Ser](/variant/cd96-p-pro346ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 759165). 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.*