# NM_002838.5(PTPRC):c.2252T>C (p.Val751Ala)

https://sugi.bio/variant/ptprc-p-val751ala

## Summary

**PTPRC p.Val751Ala (c.2252T>C)** is classified **Uncertain significance** in PTPRC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-19). AlphaMissense: likely pathogenic (0.9735); Very rare (popmax 0.00501%, amr); Associated with immunodeficiency 104.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1464440498 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00501%, amr)

## For patients & families {#patients}

This is a change in the PTPRC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Val751Ala |
| Coding change (HGVS c.) | c.2252T>C |
| MANE Select transcript | [NM_002838](https://www.ncbi.nlm.nih.gov/nuccore/NM_002838) |
| dbSNP | [rs1464440498](https://www.ncbi.nlm.nih.gov/snp/rs1464440498/) |
| Variant type | single nucleotide variant |
| Location | chr1:198734400-198734400 (GRCh38) |
| ClinVar | [VCV1416699](https://www.ncbi.nlm.nih.gov/clinvar/variation/1416699/) |

**All HGVS expressions:** `LRG_95:g.100306T>C`, `LRG_95t1:c.2252T>C`, `NC_000001.10:g.198703529T>C`, `NC_000001.11:g.198734400T>C`, `NG_007730.2:g.100306T>C`, `NM_002838.5:c.2252T>C`, `NM_080921.4:c.1769T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9735)
- REVEL 0.509 (indeterminate)
- SaProt LLR -7.481 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- Conservation: phyloP 7.843, GERP 2.3, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in PTPRC (of 7,754 modeled).
- CADD: **PHRED 27.1**. 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 0.89** across the covering region of the MANE Select transcript (198,639,269–198,741,873), spanning 102,604 bp. Chi-square p 0.0009. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00501%** (amr) · FAF95 0.00133% · FAF99 0.000669% · 3/59,822 in the highest group · 4/1,610,966 alleles overall — very rare (popmax 0.00501%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00501% | 19,941 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,302 |

*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 **751** lies in a UniProt-annotated variant site (in imd105); the tyrosine-protein phosphatase 1 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.Val751Ala falls in the tyrosine-protein phosphatase 1 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-19.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-19 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Immunodeficiency 104, 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, IMMUNODEFICIENCY 104, SEVERE COMBINED, Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-positive.

## 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 1416699). 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.*