# NM_001782.3(CD72):c.242C>T (p.Ala81Val)

https://sugi.bio/variant/cd72-p-ala81val

## Summary

**CD72 p.Ala81Val (c.242C>T)** is classified **Uncertain significance** in CD72 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely benign (0.0926); Ultra-rare (popmax 0.0148%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0148%, amr)

## For patients & families {#patients}

This is a change in the CD72 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 | [CD72](https://sugi.bio/atlas/gene/CD72/) |
| Protein change (HGVS p.) | p.Ala81Val |
| Coding change (HGVS c.) | c.242C>T |
| MANE Select transcript | [NM_001782](https://www.ncbi.nlm.nih.gov/nuccore/NM_001782) |
| Variant type | single nucleotide variant |
| Location | chr9:35617196-35617196 (GRCh38) |
| ClinVar | [VCV3488168](https://www.ncbi.nlm.nih.gov/clinvar/variation/3488168/) |

**All HGVS expressions:** `NC_000009.11:g.35617193G>A`, `NC_000009.12:g.35617196G>A`, `NG_181155.1:g.29G>A`, `NM_001782.3:c.242C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0926)
- REVEL 0.093 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.06 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.792, GERP -0.744, phastCons 0.955 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 17.12**. 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 0.96** across the covering region of the MANE Select transcript (35,610,627–35,618,303), spanning 7,676 bp. Chi-square p 0.39. 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>C, Δ0.25 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 **0.0148%** (amr) · FAF95 0.00736% · FAF99 0.00539% · 8/53,902 in the highest group · 24/1,568,362 alleles overall — ultra-rare (popmax 0.0148%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0148% | 6,738 |
| Remaining individuals (not grpmax-eligible) | 0.00659% | 15,168 |
| European (non-Finnish) | 0.00104% | 96,348 |

*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}

**CD72** population constraint: LOEUF 0.832, pLI 0.00024444, missense-Z 0.60419. *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 76.85, 48% of residues very-high.

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

*Describes the biological roles of CD72 (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:** CD72's established molecular role includes transmembrane signaling receptor activity.


### Pathways affected {#pathways}

CD72 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Other semaphorin interactions](https://reactome.org/content/detail/R-HSA-416700) | curated |

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

**Molecular function:** transmembrane signaling receptor activity, receptor ligand activity.

**Biological process:** negative regulation of B cell receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-02.

**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 | 2024-07-02 |

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

## Similar variants {#similar}

Related CD72 variant pages (same residue, condition, or type): [CD72 p.Ala180Glu](/variant/cd72-p-ala180glu), [CD72 p.Ala269Val](/variant/cd72-p-ala269val), [CD72 p.Ala2Gly](/variant/cd72-p-ala2gly), [CD72 p.Ala4Thr](/variant/cd72-p-ala4thr), [CD72 p.Arg144Cys](/variant/cd72-p-arg144cys), [CD72 p.Arg161Lys](/variant/cd72-p-arg161lys), [CD72 p.Arg84Leu](/variant/cd72-p-arg84leu), [CD72 p.Asp191Gly](/variant/cd72-p-asp191gly).

### 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 3488168). 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.*