# NM_000591.4(CD14):c.886C>G (p.Pro296Ala)

https://sugi.bio/variant/cd14-p-pro296ala

## Summary

**CD14 p.Pro296Ala (c.886C>G)** is classified **Uncertain significance** in CD14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: ambiguous (0.4602); Very rare (popmax 0.00169%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00169%, nfe)

## For patients & families {#patients}

This is a change in the CD14 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CD14](https://sugi.bio/atlas/gene/CD14/) |
| Protein change (HGVS p.) | p.Pro296Ala |
| Coding change (HGVS c.) | c.886C>G |
| MANE Select transcript | [NM_000591](https://www.ncbi.nlm.nih.gov/nuccore/NM_000591) |
| Variant type | single nucleotide variant |
| Location | chr5:140632098-140632098 (GRCh38) |
| ClinVar | [VCV3997970](https://www.ncbi.nlm.nih.gov/clinvar/variation/3997970/) |

**All HGVS expressions:** `NC_000005.10:g.140632098G>C`, `NC_000005.9:g.140011683G>C`, `NG_023178.1:g.6604C>G`, `NG_106007.1:g.381G>C`, `NM_000591.4:c.886C>G`, `NM_001040021.3:c.886C>G`, `NM_001174104.2:c.886C>G`, `NM_001174105.2:c.886C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.4602) — no call either way
- REVEL 0.26 (benign-leaning)
- SaProt LLR -11.504 (damaging)
- → **In-silico consensus:** SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate
- Conservation: phyloP 11.414, GERP 2.14, phastCons 1 — highly conserved
- CADD: **PHRED 27.5**. 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 0.96** across the covering region of the MANE Select transcript (140,631,859–140,633,071), spanning 1,212 bp. Chi-square p 0.37. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00169%** (nfe) · FAF95 0.00111% · FAF99 0.0009% · 20/1,180,046 in the highest group · 24/1,614,088 alleles overall — very rare (popmax 0.00169%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,245 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,011 |
| European (non-Finnish) (grpmax) | 0.00169% | 59,002 |

Remaining individuals 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}

**CD14** population constraint: LOEUF 1.944, pLI 0.0029381, missense-Z 0.88632. *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 **296** lies in the 'required for response to bacterial lipopolysaccharide (lps)' region.

AlphaFold model confidence (whole protein): pLDDT 85.36, 72% of residues very-high.

**1 experimental structure(s)** (PDB): [4GLP](https://www.rcsb.org/structure/4GLP).

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

*Describes the biological roles of CD14 (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:** CD14's established molecular role includes lipopolysaccharide binding. p.Pro296Ala falls in the required for response to bacterial lipopolysaccharide (lps) region. In Reactome, CD14 is annotated in disease pathway(s) including **Dengue Virus Attachment and Entry**, **IRAK4 deficiency (TLR2/4)**.

**Disease mechanism (Reactome):** CD14 loss or alteration is curated in [Dengue Virus Attachment and Entry](https://reactome.org/content/detail/R-HSA-9918485), [IRAK4 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5603041), [MyD88 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5602498).

### Pathways affected {#pathways}

CD14 participates in **22 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus Attachment and Entry](https://reactome.org/content/detail/R-HSA-9918485) | curated |
| ⚕ [IRAK4 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5603041) | curated |
| ⚕ [MyD88 deficiency (TLR2/4)](https://reactome.org/content/detail/R-HSA-5602498) | curated |
| ⚕ [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110) | curated |
| ⚕ [Respiratory syncytial virus (RSV) attachment and entry](https://reactome.org/content/detail/R-HSA-9820960) | curated |
| [Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)](https://reactome.org/content/detail/R-HSA-936964) | curated |
| [Caspase activation via Death Receptors in the presence of ligand](https://reactome.org/content/detail/R-HSA-140534) | curated |
| [Differentiation of Circulating Monocytes](https://reactome.org/content/detail/R-HSA-9968734) | curated |
| [ER-Phagosome pathway](https://reactome.org/content/detail/R-HSA-1236974) | curated |
| [IKK complex recruitment mediated by RIP1](https://reactome.org/content/detail/R-HSA-937041) | curated |
| [IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation](https://reactome.org/content/detail/R-HSA-975163) | curated |
| [MyD88-independent TLR4 cascade ](https://reactome.org/content/detail/R-HSA-166166) | curated |
| [MyD88:MAL(TIRAP) cascade initiated on plasma membrane](https://reactome.org/content/detail/R-HSA-166058) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 ](https://reactome.org/content/detail/R-HSA-9824878) | curated |
| [Regulation of TLR by endogenous ligand](https://reactome.org/content/detail/R-HSA-5686938) | curated |
| [TRAF6-mediated induction of TAK1 complex within TLR4 complex](https://reactome.org/content/detail/R-HSA-937072) | curated |
| [TRIF-mediated programmed cell death](https://reactome.org/content/detail/R-HSA-2562578) | curated |
| [Toll Like Receptor 4 (TLR4) Cascade](https://reactome.org/content/detail/R-HSA-166016) | curated |
| [Toll Like Receptor TLR1:TLR2 Cascade](https://reactome.org/content/detail/R-HSA-168179) | curated |
| [Toll Like Receptor TLR6:TLR2 Cascade](https://reactome.org/content/detail/R-HSA-168188) | curated |
| [Transfer of LPS from LBP carrier to CD14](https://reactome.org/content/detail/R-HSA-166020) | curated |

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

**Molecular function:** lipopolysaccharide binding, lipopolysaccharide immune receptor activity, lipoteichoic acid binding, molecular carrier activity.

**Biological process:** cell surface pattern recognition receptor signaling pathway, positive regulation of interleukin-8 production, positive regulation of tumor necrosis factor production, toll-like receptor 4 signaling pathway, cellular response to molecule of bacterial origin, cellular response to lipopolysaccharide.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-10 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CD14 variant pages (same residue, condition, or type): [CD14 p.Ala114Thr](/variant/cd14-p-ala114thr), [CD14 p.Ala143Gly](/variant/cd14-p-ala143gly), [CD14 p.Ala184Thr](/variant/cd14-p-ala184thr), [CD14 p.Ala269Thr](/variant/cd14-p-ala269thr), [CD14 p.Ala75Gly](/variant/cd14-p-ala75gly), [CD14 p.Ala98Ser](/variant/cd14-p-ala98ser), [CD14 p.Arg111His](/variant/cd14-p-arg111his), [CD14 p.Arg117Ser](/variant/cd14-p-arg117ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3997970). 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.*