# NM_014207.4(CD5):c.301C>T (p.Pro101Ser)

https://sugi.bio/variant/cd5-p-pro101ser

## Summary

**CD5 p.Pro101Ser (c.301C>T)** is classified **Uncertain significance** in CD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: likely benign (0.0847); Very rare (popmax 0.00801%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs759135823 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00801%, afr)

## For patients & families {#patients}

This is a change in the CD5 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 | [CD5](https://sugi.bio/atlas/gene/CD5/) |
| Protein change (HGVS p.) | p.Pro101Ser |
| Coding change (HGVS c.) | c.301C>T |
| MANE Select transcript | [NM_014207](https://www.ncbi.nlm.nih.gov/nuccore/NM_014207) |
| dbSNP | [rs759135823](https://www.ncbi.nlm.nih.gov/snp/rs759135823/) |
| Variant type | single nucleotide variant |
| Location | chr11:61118381-61118381 (GRCh38) |
| ClinVar | [VCV2601070](https://www.ncbi.nlm.nih.gov/clinvar/variation/2601070/) |

**All HGVS expressions:** `NC_000011.10:g.61118381C>T`, `NC_000011.9:g.60885853C>T`, `NM_001346456.2:c.130C>T`, `NM_014207.4:c.301C>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** (0.0847)
- REVEL 0.027 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.55 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -3.637, GERP -3.01 — fast-evolving / accelerated position
- CADD: **PHRED 0.14**. 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 0.86** across the covering region of the MANE Select transcript (61,102,561–61,125,836), spanning 23,275 bp. Chi-square p 0.00031. 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>G, Δ0.34 acceptor 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 **0.00801%** (afr) · FAF95 0.00347% · FAF99 0.00228% · 6/74,944 in the highest group · 9/1,614,118 alleles overall — very rare (popmax 0.00801%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00801% | 12,491 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |
| European (non-Finnish) | 0.000169% | 590,016 |

*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}

**CD5** population constraint: LOEUF 0.835, pLI 1.2515e-07, missense-Z 1.3463. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **101** lies in a turn; the srcr 1 domain.

AlphaFold model confidence (whole protein): pLDDT 73.32, 32% of residues very-high.

**4 experimental structure(s)** (PDB): [2JA4](https://www.rcsb.org/structure/2JA4), [2JOP](https://www.rcsb.org/structure/2JOP), [2JP0](https://www.rcsb.org/structure/2JP0), [2OTT](https://www.rcsb.org/structure/2OTT).

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

*Describes the biological roles of CD5 (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:** CD5's established molecular role includes signaling receptor activity. p.Pro101Ser falls in the srcr 1 domain.


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

**Molecular function:** signaling receptor 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 2023-08-22.

**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 | 2023-08-22 |

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

## Similar variants {#similar}

Related CD5 variant pages (same residue, condition, or type): [CD5 p.Pro101Ala](/variant/cd5-p-pro101ala), [CD5 p.Ala471Val](/variant/cd5-p-ala471val), [CD5 p.Pro224Leu](/variant/cd5-p-pro224leu), [CD5 p.Ala295Ser](/variant/cd5-p-ala295ser), [CD5 p.Ala492Asp](/variant/cd5-p-ala492asp), [CD5 p.Ala492Val](/variant/cd5-p-ala492val), [CD5 p.Ala77Val](/variant/cd5-p-ala77val), [CD5 p.Arg228Gln](/variant/cd5-p-arg228gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2601070). 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.*