# NM_001768.7(CD8A):c.514G>A (p.Val172Met)

https://sugi.bio/variant/cd8a-p-val172met

## Summary

**CD8A p.Val172Met (c.514G>A)** is classified **Uncertain significance** in CD8A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-29). AlphaMissense: likely benign (0.1443); Very rare (popmax 7.51e-05%); Associated with susceptibility to respiratory infections associated with CD8alpha chain mutation.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1673181666 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 7.51e-05%)

## For patients & families {#patients}

This is a change in the CD8A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to susceptibility to respiratory infections associated with CD8alpha chain mutation.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (Europe) |
| Diagnostic panels | CD8A is a diagnostic-grade gene on 1 Genomics England panel |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017047/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD8A](https://sugi.bio/atlas/gene/CD8A/) |
| Protein change (HGVS p.) | p.Val172Met |
| Coding change (HGVS c.) | c.514G>A |
| MANE Select transcript | [NM_001768](https://www.ncbi.nlm.nih.gov/nuccore/NM_001768) |
| dbSNP | [rs1673181666](https://www.ncbi.nlm.nih.gov/snp/rs1673181666/) |
| Variant type | single nucleotide variant |
| Location | chr2:86789640-86789640 (GRCh38) |
| ClinVar | [VCV2834635](https://www.ncbi.nlm.nih.gov/clinvar/variation/2834635/) |

**All HGVS expressions:** `LRG_44:g.23757G>A`, `LRG_44t1:c.514G>A`, `NC_000002.11:g.87016763C>T`, `NC_000002.12:g.86789640C>T`, `NG_011608.2:g.23757G>A`, `NG_095773.1:g.127C>T`, `NM_001145873.1:c.514G>A`, `NM_001382698.1:c.514G>A`, `NM_001768.7:c.514G>A`, `NM_171827.4:c.514G>A`, `NR_027353.2:n.955G>A`, `NR_168478.1:n.2098G>A`, `NR_168480.1:n.1944G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1443)
- REVEL 0.166 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.313 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.31) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.996, GERP 0.519, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.5**. 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 1.13** across the covering region of the MANE Select transcript (86,785,923–86,790,825), spanning 4,902 bp. Chi-square p 0.024. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.31**, acceptor gain **0.00**, donor gain **0.05**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.05**.
  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.*
- Pangolin: Δ**0.41** (loss), gain 0.01 / loss 0.41. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): global (via dbSNP) **7.51e-05%** · 1/1,331,486 alleles overall — very rare (popmax 7.51e-05%).

*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}

**CD8A** population constraint: LOEUF 1.496, pLI 2.5309e-09, missense-Z -1.2645; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **susceptibility to respiratory infections associated with CD8alpha chain mutation** — Limited (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.03, 49% of residues very-high.

**8 experimental structure(s)** (PDB): [1AKJ](https://www.rcsb.org/structure/1AKJ), [1CD8](https://www.rcsb.org/structure/1CD8), [1Q69](https://www.rcsb.org/structure/1Q69), [2HP4](https://www.rcsb.org/structure/2HP4), [3QZW](https://www.rcsb.org/structure/3QZW), [7UMG](https://www.rcsb.org/structure/7UMG) — incl. mutant structure 2HP4.

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

*Describes the biological roles of CD8A (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:** CD8A's established molecular role includes MHC class I protein complex binding.


### Pathways affected {#pathways}

CD8A participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |

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

**Molecular function:** MHC class I protein complex binding.

**Biological process:** T cell activation, T cell receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-29.

**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 | 2024-01-29 |

## Associated conditions {#conditions}

[susceptibility to respiratory infections associated with CD8alpha chain mutation](https://sugi.bio/atlas/disease/susceptibility-to-respiratory-infections-associated-with-cd8alpha-chain-mutation/).

**Reported phenotype names (ClinVar):** Susceptibility to respiratory infections associated with CD8alpha chain mutation, IMMUNODEFICIENCY 116, Cd8 deficiency, familial.

## Similar variants {#similar}

Related CD8A variant pages (same residue, condition, or type): [CD8A c.403+4C>G](/variant/cd8a-c-403-plus-4c-g), [CD8A c.626-2A>T](/variant/cd8a-c-626-minus-2a-t), [CD8A p.Arg165Leu](/variant/cd8a-p-arg165leu), [CD8A p.Arg165Pro](/variant/cd8a-p-arg165pro), [CD8A p.His127Tyr](/variant/cd8a-p-his127tyr), [CD8A p.His208Leu](/variant/cd8a-p-his208leu), [CD8A p.Leu10Arg](/variant/cd8a-p-leu10arg), [CD8A p.Pro130Arg](/variant/cd8a-p-pro130arg).

### 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 2834635). 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.*