# NM_005755.3(EBI3):c.385C>T (p.Pro129Ser)

https://sugi.bio/variant/ebi3-p-pro129ser

## Summary

**EBI3 p.Pro129Ser (c.385C>T)** is classified **Uncertain significance** in EBI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: likely pathogenic (0.9121); Very rare (popmax 0.00223%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2512614999 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the EBI3 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 | [EBI3](https://sugi.bio/atlas/gene/EBI3/) |
| Protein change (HGVS p.) | p.Pro129Ser |
| Coding change (HGVS c.) | c.385C>T |
| MANE Select transcript | [NM_005755](https://www.ncbi.nlm.nih.gov/nuccore/NM_005755) |
| dbSNP | [rs2512614999](https://www.ncbi.nlm.nih.gov/snp/rs2512614999/) |
| Variant type | single nucleotide variant |
| Location | chr19:4234672-4234672 (GRCh38) |
| ClinVar | [VCV2269736](https://www.ncbi.nlm.nih.gov/clinvar/variation/2269736/) |

**All HGVS expressions:** `NC_000019.10:g.4234672C>T`, `NC_000019.9:g.4234669C>T`, `NM_005755.3:c.385C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9121)
- REVEL 0.459 (indeterminate)
- SaProt LLR -11.101 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 4.396, GERP 1.44, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in EBI3 (of 1,334 modeled).
- CADD: **PHRED 23.6**. 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 1.05** across the covering region of the MANE Select transcript (4,229,551–4,237,085), spanning 7,534 bp. Chi-square p 0.34. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.23 acceptor gain), 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 **0.00223%** (eas) · 1/44,862 in the highest group · 1/1,612,678 alleles overall — very rare (popmax 0.00223%, eas).

*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}

**EBI3** population constraint: LOEUF 1.373, pLI 6.3142e-07, missense-Z -0.78138. *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 **129** lies in the fibronectin type-iii 1 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 88.34, 72% of residues very-high.

**4 experimental structure(s)** (PDB): [7U7N](https://www.rcsb.org/structure/7U7N), [7ZXK](https://www.rcsb.org/structure/7ZXK), [8D85](https://www.rcsb.org/structure/8D85), [8XWY](https://www.rcsb.org/structure/8XWY).

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

*Describes the biological roles of EBI3 (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:** EBI3's established molecular role includes cytokine receptor activity. p.Pro129Ser falls in the fibronectin type-iii 1 domain.


### Pathways affected {#pathways}

EBI3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interleukin-27 signaling](https://reactome.org/content/detail/R-HSA-9020956) | curated |
| [Interleukin-35 Signalling](https://reactome.org/content/detail/R-HSA-8984722) | curated |

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

**Molecular function:** cytokine receptor activity.

**Biological process:** regulation of T cell proliferation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-04.

**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 | 2022-01-04 |

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

## Similar variants {#similar}

Related EBI3 variant pages (same residue, condition, or type): [EBI3 c.200+3C>T](/variant/ebi3-c-200-plus-3c-t), [EBI3 p.Ala13Thr](/variant/ebi3-p-ala13thr), [EBI3 p.Ala205Ser](/variant/ebi3-p-ala205ser), [EBI3 p.Ala27Val](/variant/ebi3-p-ala27val), [EBI3 p.Arg136Cys](/variant/ebi3-p-arg136cys), [EBI3 p.Arg136His](/variant/ebi3-p-arg136his), [EBI3 p.Arg143His](/variant/ebi3-p-arg143his), [EBI3 p.Arg168Cys](/variant/ebi3-p-arg168cys).

### 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 2269736). 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.*