# NM_001768.7(CD8A):c.509dup (p.Ala171fs)

https://sugi.bio/variant/cd8a-p-ala171fs

## Summary

**CD8A p.Ala171fs (c.509dup)** is classified **Uncertain significance** in CD8A (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-11). Very rare (popmax 0.000179%, nfe); Associated with susceptibility to respiratory infections associated with CD8alpha chain mutation.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1673182671 · 1 submitter · 1 linked condition · very rare (popmax 0.000179%, nfe)

## 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.Ala171fs |
| Coding change (HGVS c.) | c.509dup |
| MANE Select transcript | [NM_001768](https://www.ncbi.nlm.nih.gov/nuccore/NM_001768) |
| dbSNP | [rs1673182671](https://www.ncbi.nlm.nih.gov/snp/rs1673182671/) |
| Variant type | Duplication |
| Location | chr2:86789644-86789645 (GRCh38) |
| ClinVar | [VCV1009961](https://www.ncbi.nlm.nih.gov/clinvar/variation/1009961/) |

**All HGVS expressions:** `LRG_44:g.23752dup`, `NC_000002.11:g.87016773dup`, `NC_000002.12:g.86789650dup`, `NG_011608.2:g.23752dup`, `NM_001145873.1:c.509dup`, `NM_001382698.1:c.509dup`, `NM_001768.7:c.509dup`, `NM_171827.4:c.509dup`, `NR_027353.2:n.950dup`, `NR_168478.1:n.2093dup`, `NR_168480.1:n.1939dup`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 0.031, GERP -0.558 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.496, pLI 2.5309e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 6**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 22.4**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **simple_repeat** ((CCGCCC)n). The alignment of this duplication is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **0.000179%** (nfe) · FAF95 3e-05% · FAF99 1.1e-05% · 2/1,118,832 in the highest group · 4/1,478,570 alleles overall — very rare (popmax 0.000179%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00469% | 21,333 |
| European (non-Finnish) (grpmax) | 0.000179% | 559,416 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 2020-02-11.

**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 | 2020-02-11 |

## 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, Cd8 deficiency, familial, IMMUNODEFICIENCY 116.

## Similar variants {#similar}

Related CD8A variant pages (same residue, condition, or type): [CD8A p.Ala171Thr](/variant/cd8a-p-ala171thr), [CD8A c.656+18_656+19dup](/variant/cd8a-c-656-plus-18-656-plus-19dup), [CD8A c.41_50-20dup](/variant/cd8a-c-41-50-minus-20dup), [CD8A c.514+11dup](/variant/cd8a-c-514-plus-11dup), [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).

### 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 1009961). 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.*