# NM_000616.5(CD4):c.369C>T (p.Phe123=)

https://sugi.bio/variant/cd4-p-phe123

## Summary

**CD4 p.Phe123= (c.369C>T)** is classified **Benign** in CD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-05-31). Low-frequency (popmax 3.29%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs11064416 · 2 submitters · low-frequency (popmax 3.29%, afr)

## For patients & families {#patients}

This is a change in the CD4 gene that is classified as benign — not considered disease-causing, submitted by 2 submitters.

*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.Phe123= |
| Coding change (HGVS c.) | c.369C>T |
| MANE Select transcript | [NM_000616](https://www.ncbi.nlm.nih.gov/nuccore/NM_000616) |
| dbSNP | [rs11064416](https://www.ncbi.nlm.nih.gov/snp/rs11064416/) |
| Variant type | single nucleotide variant |
| Location | chr12:6814296-6814296 (GRCh38) |
| ClinVar | [VCV714504](https://www.ncbi.nlm.nih.gov/clinvar/variation/714504/) |

**All HGVS expressions:** `NC_000012.11:g.6923462C>T`, `NC_000012.12:g.6814296C>T`, `NG_027688.1:g.29825C>T`, `NM_000616.5:c.369C>T`, `NM_001195014.3:c.-494C>T`, `NM_001195015.3:c.-464C>T`, `NM_001195016.3:c.-451C>T`, `NM_001195017.3:c.-447+18C>T`

## 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 -0.047, GERP -2.25, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 13.28**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.35 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **3.29%** (afr) · FAF95 3.18% · FAF99 3.14% · 2,467/74,946 in the highest group · 2,907/1,613,462 alleles overall — low-frequency (popmax 3.29%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 3.29% | 30 |
| Admixed American | 0.298% | 335 |
| Remaining individuals (not grpmax-eligible) | 0.219% | 456 |
| Middle Eastern | 0.132% | 756 |
| European (non-Finnish) | 0.00949% | 10,533 |
| South Asian | 0.0033% | 30,336 |
| East Asian | 0.00223% | 44,870 |

*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 **123** lies in the ig-like v-type domain; a β-strand.

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.Phe123= falls in the ig-like v-type 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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-05-31.

**Submitter consensus:** unanimous (2/2 Benign).

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-05-31 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related CD4 variant pages (same residue, condition, or type): [CD4 p.Phe123Leu](/variant/cd4-p-phe123leu), [CD4 p.Ser352Trp](/variant/cd4-p-ser352trp), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 714504). 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.*