# NM_005816.5(CD96):c.745G>T (p.Val249Phe)

https://sugi.bio/variant/cd96-p-val249phe

## Summary

**CD96 p.Val249Phe (c.745G>T)** is classified **Uncertain significance** in CD96 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-05). AlphaMissense: likely pathogenic (0.6742); Very rare (popmax 0.000698%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1017144472 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.000698%, nfe)

## For patients & families {#patients}

This is a change in the CD96 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 | [CD96](https://sugi.bio/atlas/gene/CD96/) |
| Protein change (HGVS p.) | p.Val249Phe |
| Coding change (HGVS c.) | c.745G>T |
| MANE Select transcript | [NM_005816](https://www.ncbi.nlm.nih.gov/nuccore/NM_005816) |
| dbSNP | [rs1017144472](https://www.ncbi.nlm.nih.gov/snp/rs1017144472/) |
| Variant type | single nucleotide variant |
| Location | chr3:111579228-111579228 (GRCh38) |
| ClinVar | [VCV2021895](https://www.ncbi.nlm.nih.gov/clinvar/variation/2021895/) |

**All HGVS expressions:** `NC_000003.11:g.111298075G>T`, `NC_000003.12:g.111579228G>T`, `NG_012156.2:g.42150G>T`, `NM_001318889.2:c.745G>T`, `NM_001410800.1:c.745G>T`, `NM_005816.5:c.745G>T`, `NM_198196.3:c.793G>T`, `NR_134917.2:n.797G>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.6742)
- REVEL 0.566 (indeterminate)
- SaProt LLR -13.555 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 9.581, GERP 1.62, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **V265F** vs ClinVar **V249F**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in CD96 (of 3,437 modeled).
- 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 1.10** across the covering region of the MANE Select transcript (111,542,249–111,649,803), spanning 107,554 bp. Chi-square p 0.013. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.38 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000698%** (nfe) · FAF95 0.0003% · FAF99 0.000217% · 8/1,146,020 in the highest group · 8/1,576,874 alleles overall — very rare (popmax 0.000698%, nfe).

*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}


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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-05 |

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

## Similar variants {#similar}

Related CD96 variant pages (same residue, condition, or type): [CD96 p.Val249=](/variant/cd96-p-val249), [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).

### 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 2026-10-14); 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 2021895). 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.*