# NM_002838.5(PTPRC):c.2925T>C (p.Ser975=)

https://sugi.bio/variant/ptprc-p-ser975

## Summary

**PTPRC p.Ser975= (c.2925T>C)** is classified **Likely benign** in PTPRC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-07). Absent from gnomAD v4.1; Associated with immunodeficiency 104.

**At a glance:** Likely benign · review: Single submitter · rsID rs2528023395 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PTPRC gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to immunodeficiency 104.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018293/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PTPRC](https://sugi.bio/atlas/gene/PTPRC/) |
| Protein change (HGVS p.) | p.Ser975= |
| Coding change (HGVS c.) | c.2925T>C |
| MANE Select transcript | [NM_002838](https://www.ncbi.nlm.nih.gov/nuccore/NM_002838) |
| dbSNP | [rs2528023395](https://www.ncbi.nlm.nih.gov/snp/rs2528023395/) |
| Variant type | single nucleotide variant |
| Location | chr1:198748186-198748186 (GRCh38) |
| ClinVar | [VCV2694180](https://www.ncbi.nlm.nih.gov/clinvar/variation/2694180/) |

**All HGVS expressions:** `LRG_95:g.114092T>C`, `LRG_95t1:c.2925T>C`, `NC_000001.10:g.198717315T>C`, `NC_000001.11:g.198748186T>C`, `NG_007730.2:g.114092T>C`, `NM_002838.5:c.2925T>C`, `NM_080921.4:c.2442T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.31) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.34, GERP -2.06, phastCons 0.007 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.044**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.31**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 17 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- 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.*

## Gene constraint & dosage {#gene-context}

**PTPRC** population constraint: LOEUF 0.343, pLI 1, missense-Z 1.9632. *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):

- **immunodeficiency 104** — Definitive (AR)

## Protein context {#protein}

Residue **975** lies in a modified residue (phosphoserine); a UniProt-annotated variant site (in imd105); the tyrosine-protein phosphatase 2 domain.

AlphaFold model confidence (whole protein): pLDDT 77.22, 51% of residues very-high.

**6 experimental structure(s)** (PDB): [1YGR](https://www.rcsb.org/structure/1YGR), [1YGU](https://www.rcsb.org/structure/1YGU), [5FMV](https://www.rcsb.org/structure/5FMV), [5FN6](https://www.rcsb.org/structure/5FN6), [5FN7](https://www.rcsb.org/structure/5FN7), [8VSE](https://www.rcsb.org/structure/8VSE).

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

*Describes the biological roles of PTPRC (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:** PTPRC's established molecular role includes protein tyrosine phosphatase activity. p.Ser975= falls in the tyrosine-protein phosphatase 2 domain.


### Pathways affected {#pathways}

PTPRC participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Other semaphorin interactions](https://reactome.org/content/detail/R-HSA-416700) | curated |
| [Phosphorylation of CD3 and TCR zeta chains](https://reactome.org/content/detail/R-HSA-202427) | curated |

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

**Molecular function:** protein tyrosine phosphatase activity, transmembrane receptor protein tyrosine phosphatase activity, protein kinase binding, protein tyrosine kinase inhibitor activity, ankyrin binding, spectrin binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, hematopoietic progenitor cell differentiation, positive regulation of immunoglobulin production, negative regulation of protein kinase activity, negative regulation of cell adhesion involved in substrate-bound cell migration, positive regulation of B cell proliferation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-07.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-07 |

## Associated conditions {#conditions}

[immunodeficiency 104](https://sugi.bio/atlas/disease/immunodeficiency-104/).

**Reported phenotype names (ClinVar):** Immunodeficiency 104, Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-positive, IMMUNODEFICIENCY 104, SEVERE COMBINED, SCID, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-POSITIVE, NK CELL-POSITIVE, Severe Combined Immune Deficiency, Autosomal Recessive, TCell -Negative, B Cell-Positive, NK Cell-Positive, IL7R-Related.

## Similar variants {#similar}

Related PTPRC variant pages (same residue, condition, or type): [PTPRC c.583+1G>A](/variant/ptprc-c-583-plus-1g-a), [PTPRC c.583+1G>T](/variant/ptprc-c-583-plus-1g-t), [PTPRC p.Arg890Ter](/variant/ptprc-p-arg890ter), [PTPRC c.1830-3C>T](/variant/ptprc-c-1830-minus-3c-t), [PTPRC c.3509+5G>A](/variant/ptprc-c-3509-plus-5g-a), [PTPRC p.Ala113Ser](/variant/ptprc-p-ala113ser), [PTPRC p.Ala191Val](/variant/ptprc-p-ala191val), [PTPRC p.Ala60Thr](/variant/ptprc-p-ala60thr).

### 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 2694180). 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.*