# NM_001778.4(CD48):c.686G>C (p.Trp229Ser)

https://sugi.bio/variant/cd48-p-trp229ser

## Summary

**CD48 p.Trp229Ser (c.686G>C)** is classified **Uncertain significance** in CD48 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-11). AlphaMissense: likely benign (0.2506); Very rare (popmax 0.00223%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1056901858 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CD48 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 | [CD48](https://sugi.bio/atlas/gene/CD48/) |
| Protein change (HGVS p.) | p.Trp229Ser |
| Coding change (HGVS c.) | c.686G>C |
| MANE Select transcript | [NM_001778](https://www.ncbi.nlm.nih.gov/nuccore/NM_001778) |
| dbSNP | [rs1056901858](https://www.ncbi.nlm.nih.gov/snp/rs1056901858/) |
| Variant type | single nucleotide variant |
| Location | chr1:160679098-160679098 (GRCh38) |
| ClinVar | [VCV2288671](https://www.ncbi.nlm.nih.gov/clinvar/variation/2288671/) |

**All HGVS expressions:** `NC_000001.10:g.160648888C>G`, `NC_000001.11:g.160679098C>G`, `NM_001778.4:c.686G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2506)
- REVEL 0.178 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.001 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.06, GERP 0.583, phastCons 0.98 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.5**. 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 1.07** across the covering region of the MANE Select transcript (160,679,055–160,711,763), spanning 32,708 bp. Chi-square p 0.23. 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 (C>T, Δ0.25 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 (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/44,884 in the highest group · 4/1,461,860 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |
| East Asian (grpmax) | 0.00223% | 44,884 |
| European (non-Finnish) | 0.000169% | 590,009 |

Ashkenazi Jewish 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}

**CD48** population constraint: LOEUF 1.31, pLI 5.0268e-07, missense-Z -0.062033. *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 83.20, 61% of residues very-high.

**1 experimental structure(s)** (PDB): [2EDO](https://www.rcsb.org/structure/2EDO).

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

*Describes the biological roles of CD48 (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:** CD48's established molecular role includes receptor ligand activity.


### Pathways affected {#pathways}

CD48 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) | curated |

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

**Molecular function:** receptor ligand activity.

**Biological process:** natural killer cell activation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-11.

**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 | 2022-05-11 |

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

## Similar variants {#similar}

Related CD48 variant pages (same residue, condition, or type): [CD48 p.Thr216Ile](/variant/cd48-p-thr216ile), [CD48 c.652+73G>T](/variant/cd48-c-652-plus-73g-t), [CD48 p.Gln90=](/variant/cd48-p-gln90), [CD48 p.Leu30=](/variant/cd48-p-leu30), [CD48 p.Thr233=](/variant/cd48-p-thr233), [CD48 p.Ala93Thr](/variant/cd48-p-ala93thr), [CD48 p.Arg192Met](/variant/cd48-p-arg192met), [CD48 p.Asn178Lys](/variant/cd48-p-asn178lys).

### 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 2288671). 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.*