# NM_000616.5(CD4):c.799A>G (p.Thr267Ala)

https://sugi.bio/variant/cd4-p-thr267ala

## Summary

**CD4 p.Thr267Ala (c.799A>G)** is classified **Uncertain significance** in CD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-13). AlphaMissense: likely benign (0.0886); Very rare (popmax 0.0011%, sas); Associated with Okt4 epitope deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1325448082 · 1 submitter · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the CD4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Okt4 epitope deficiency.

*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 | [CD4](https://sugi.bio/atlas/gene/CD4/) |
| Protein change (HGVS p.) | p.Thr267Ala |
| Coding change (HGVS c.) | c.799A>G |
| MANE Select transcript | [NM_000616](https://www.ncbi.nlm.nih.gov/nuccore/NM_000616) |
| dbSNP | [rs1325448082](https://www.ncbi.nlm.nih.gov/snp/rs1325448082/) |
| Variant type | single nucleotide variant |
| Location | chr12:6816247-6816247 (GRCh38) |
| ClinVar | [VCV626076](https://www.ncbi.nlm.nih.gov/clinvar/variation/626076/) |

**All HGVS expressions:** `NC_000012.11:g.6925413A>G`, `NC_000012.12:g.6816247A>G`, `NG_027688.1:g.31776A>G`, `NM_000616.5:c.799A>G`, `NM_001195014.3:c.262A>G`, `NM_001195015.3:c.-21A>G`, `NM_001195016.3:c.-21A>G`, `NM_001195017.3:c.-21A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0886)
- REVEL 0.028 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.85 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -3.375, GERP -4.12 — fast-evolving / accelerated position
- CADD: **PHRED 0.098**. 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 0.83** across the covering region of the MANE Select transcript (6,800,139–6,819,326), spanning 19,187 bp. Chi-square p 7.9e-05. 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 **0.0011%** (sas) · FAF95 0.000183% · FAF99 0.00012% · 1/91,088 in the highest group · 7/1,614,082 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,088 |
| European (non-Finnish) | 0.000508% | 196,673 |

*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}

**CD4** population constraint: LOEUF 0.673, pLI 0.0060803, missense-Z 1.6912. *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 **267** lies in the ig-like c2-type 2 domain.

AlphaFold model confidence (whole protein): pLDDT 85.35, 65% of residues very-high.

**84 experimental structure(s)** (PDB): [1CDH](https://www.rcsb.org/structure/1CDH), [1CDI](https://www.rcsb.org/structure/1CDI), [1CDJ](https://www.rcsb.org/structure/1CDJ), [1CDU](https://www.rcsb.org/structure/1CDU), [1CDY](https://www.rcsb.org/structure/1CDY), [1G9M](https://www.rcsb.org/structure/1G9M) — incl. mutant structure 1CDU.

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

*Describes the biological roles of CD4 (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:** CD4's established molecular role includes virus receptor activity. p.Thr267Ala falls in the ig-like c2-type 2 domain. In Reactome, CD4 is annotated in disease pathway(s) including **Binding and entry of HIV virion**, **Nef Mediated CD4 Down-regulation**.

**Disease mechanism (Reactome):** CD4 loss or alteration is curated in [Binding and entry of HIV virion](https://reactome.org/content/detail/R-HSA-173107), [Nef Mediated CD4 Down-regulation](https://reactome.org/content/detail/R-HSA-167590), [Vpu mediated degradation of CD4](https://reactome.org/content/detail/R-HSA-180534).

### Pathways affected {#pathways}

CD4 participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Binding and entry of HIV virion](https://reactome.org/content/detail/R-HSA-173107) | curated |
| ⚕ [Nef Mediated CD4 Down-regulation](https://reactome.org/content/detail/R-HSA-167590) | curated |
| ⚕ [Vpu mediated degradation of CD4](https://reactome.org/content/detail/R-HSA-180534) | curated |
| [Alpha-defensins](https://reactome.org/content/detail/R-HSA-1462054) | curated |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [Co-inhibition by PD-1](https://reactome.org/content/detail/R-HSA-389948) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [Generation of second messenger molecules](https://reactome.org/content/detail/R-HSA-202433) | curated |
| [Other interleukin signaling](https://reactome.org/content/detail/R-HSA-449836) | curated |
| [Phosphorylation of CD3 and TCR zeta chains](https://reactome.org/content/detail/R-HSA-202427) | curated |
| [Translocation of ZAP-70 to Immunological synapse](https://reactome.org/content/detail/R-HSA-202430) | curated |
| [Affinity selection of immunoglobulins](https://reactome.org/content/detail/R-HSA-9938027) | electronic |

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

**Molecular function:** virus receptor activity, zinc ion binding, lipid binding, coreceptor activity, enzyme binding, protein kinase binding.

**Biological process:** T cell differentiation, macrophage differentiation, maintenance of protein location in cell, interleukin-15-mediated signaling pathway, T cell selection, positive regulation of monocyte differentiation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-03-13.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-03-13 |
| Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[Okt4 epitope deficiency](https://sugi.bio/atlas/disease/okt4-epitope-deficiency/), [immunodeficiency 79](https://sugi.bio/atlas/disease/immunodeficiency-79/).

**Reported phenotype names (ClinVar):** Okt4 epitope deficiency, Immunodeficiency 79, T4 EPITOPE DEFICIENCY, CD4 deficiency.

## Similar variants {#similar}

Related CD4 variant pages (same residue, condition, or type): [CD4 p.Thr444Ala](/variant/cd4-p-thr444ala), [CD4 c.1346+55T>G](/variant/cd4-c-1346-plus-55t-g), [CD4 c.49+35A>G](/variant/cd4-c-49-plus-35a-g), [CD4 c.*91C>A](/variant/cd4-c-star-91c-a), [CD4 c.*92A>G](/variant/cd4-c-star-92a-g), [CD4 p.Arg265Trp](/variant/cd4-p-arg265trp), [CD4 p.Cys447=](/variant/cd4-p-cys447), [CD4 p.Ser341=](/variant/cd4-p-ser341).

### 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 626076). 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.*