# NM_031462.4(CD99L2):c.283T>C (p.Trp95Arg)

https://sugi.bio/variant/cd99l2-p-trp95arg

## Summary

**CD99L2 p.Trp95Arg (c.283T>C)** is classified **Uncertain significance** in CD99L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-07). AlphaMissense: ambiguous (0.4431); Absent from gnomAD v4.1.

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

## For patients & families {#patients}

This is a change in the CD99L2 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 | [CD99L2](https://sugi.bio/atlas/gene/CD99L2/) |
| Protein change (HGVS p.) | p.Trp95Arg |
| Coding change (HGVS c.) | c.283T>C |
| MANE Select transcript | [NM_031462](https://www.ncbi.nlm.nih.gov/nuccore/NM_031462) |
| Variant type | single nucleotide variant |
| Location | chrX:150795481-150795481 (GRCh38) |
| ClinVar | [VCV3829673](https://www.ncbi.nlm.nih.gov/clinvar/variation/3829673/) |

**All HGVS expressions:** `NC_000023.10:g.149963954A>G`, `NC_000023.11:g.150795481A>G`, `NG_021320.2:g.108336T>C`, `NM_001184808.2:c.278-17999T>C`, `NM_001242614.2:c.295T>C`, `NM_031462.4:c.283T>C`, `NM_134445.4:c.131-192T>C`, `NM_134446.4:c.136T>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** (0.4431) — no call either way
- REVEL 0.25 (benign-leaning)
- SaProt LLR -7.288 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- Conservation: phyloP 3.415, GERP -0.342, phastCons 1 — highly conserved
- CADD: **PHRED 18.63**. 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 1.15** across the covering region of the MANE Select transcript (150,769,037–150,898,588), spanning 129,551 bp. Chi-square p 0.025. 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 (A>C, Δ0.22 acceptor loss), 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: **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.*

## Protein context {#protein}

Residue **95** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 55.71, 0% of residues very-high.

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

*Describes the biological roles of CD99L2 (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}

CD99L2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cell surface interactions at the vascular wall](https://reactome.org/content/detail/R-HSA-202733) | electronic |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-07.

**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 | 2025-01-07 |

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

## Similar variants {#similar}

Related CD99L2 variant pages (same residue, condition, or type): [CD99L2 p.Asp175Asn](/variant/cd99l2-p-asp175asn), [CD99L2 c.203-9C>A](/variant/cd99l2-c-203-minus-9c-a), [CD99L2 c.68-5755G>T](/variant/cd99l2-c-68-minus-5755g-t), [CD99L2 p.Ala182Ser](/variant/cd99l2-p-ala182ser), [CD99L2 p.Arg104Lys](/variant/cd99l2-p-arg104lys), [CD99L2 p.Arg131Gln](/variant/cd99l2-p-arg131gln), [CD99L2 p.Arg135Cys](/variant/cd99l2-p-arg135cys), [CD99L2 p.Arg169Gln](/variant/cd99l2-p-arg169gln).

### 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 3829673). 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.*