# NM_014239.4(EIF2B2):c.921C>T (p.Ser307=)

https://sugi.bio/variant/eif2b2-p-ser307

## Summary

**EIF2B2 p.Ser307= (c.921C>T)** is classified **Uncertain significance** in EIF2B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-12). Very rare (popmax 0.00458%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs768467979 · 1 submitter · very rare (popmax 0.00458%, nfe)

## For patients & families {#patients}

This is a change in the EIF2B2 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 | [EIF2B2](https://sugi.bio/atlas/gene/EIF2B2/) |
| Protein change (HGVS p.) | p.Ser307= |
| Coding change (HGVS c.) | c.921C>T |
| MANE Select transcript | [NM_014239](https://www.ncbi.nlm.nih.gov/nuccore/NM_014239) |
| dbSNP | [rs768467979](https://www.ncbi.nlm.nih.gov/snp/rs768467979/) |
| Variant type | single nucleotide variant |
| Location | chr14:75009053-75009053 (GRCh38) |
| ClinVar | [VCV1913654](https://www.ncbi.nlm.nih.gov/clinvar/variation/1913654/) |

**All HGVS expressions:** `NC_000014.8:g.75475756C>T`, `NC_000014.9:g.75009053C>T`, `NG_013333.2:g.11134C>T`, `NM_014239.4:c.921C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -1.502, GERP -0.791 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.147**. 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 deltas (raw): acceptor loss **0.24**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.05**. Largest is acceptor loss, 22 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.05**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.34** (loss), gain 0.09 / loss 0.34. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00458%** (nfe) · FAF95 0.00358% · FAF99 0.00321% · 54/1,179,994 in the highest group · 61/1,613,920 alleles overall — very rare (popmax 0.00458%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,413 |
| European (non-Finnish) (grpmax) | 0.00458% | 21,852 |
| Admixed American | 0.00167% | 59,992 |

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}

**EIF2B2** population constraint: LOEUF 1.25, pLI 1.6143e-10, missense-Z 1.8987. *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):

- **leukoencephalopathy with vanishing white matter 2** — Definitive (AR)

## Protein context {#protein}

Residue **307** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 86.82, 55% of residues very-high.

**38 experimental structure(s)** (PDB): [6CAJ](https://www.rcsb.org/structure/6CAJ), [6EZO](https://www.rcsb.org/structure/6EZO), [6K71](https://www.rcsb.org/structure/6K71), [6K72](https://www.rcsb.org/structure/6K72), [6O81](https://www.rcsb.org/structure/6O81), [6O85](https://www.rcsb.org/structure/6O85).

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

*Describes the biological roles of EIF2B2 (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:** EIF2B2's established molecular role includes guanyl-nucleotide exchange factor activity.


### Pathways affected {#pathways}

EIF2B2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Recycling of eIF2:GDP](https://reactome.org/content/detail/R-HSA-72731) | curated |

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

**Molecular function:** guanyl-nucleotide exchange factor activity, ATP binding, GTP binding.

**Biological process:** ovarian follicle development, cytoplasmic translational initiation, translational initiation, central nervous system development, oligodendrocyte development, myelination.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-12.

**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 | 2022-03-12 |

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

## Similar variants {#similar}

Related EIF2B2 variant pages (same residue, condition, or type): [EIF2B2 c.285-1G>A](/variant/eif2b2-c-285-minus-1g-a), [EIF2B2 c.832-2A>G](/variant/eif2b2-c-832-minus-2a-g), [EIF2B2 p.Arg172Ter](/variant/eif2b2-p-arg172ter), [EIF2B2 p.Arg183Ter](/variant/eif2b2-p-arg183ter), [EIF2B2 p.Glu213Gly](/variant/eif2b2-p-glu213gly), [EIF2B2 p.Glu304Ter](/variant/eif2b2-p-glu304ter), [EIF2B2 p.Gly200Val](/variant/eif2b2-p-gly200val), [EIF2B2 p.Lys273Arg](/variant/eif2b2-p-lys273arg).

### 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 1913654). 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.*