# NM_003754.3(EIF3F):c.21A>G (p.Pro7=)

https://sugi.bio/variant/eif3f-p-pro7

## Summary

**EIF3F p.Pro7= (c.21A>G)** is classified **Likely benign** in EIF3F (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-01). Rare (popmax 0.13%, nfe).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs148453570 · 3 submitters · rare (popmax 0.13%, nfe)

## For patients & families {#patients}

This is a change in the EIF3F gene that is classified as likely benign — not considered disease-causing, submitted by 3 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 | [EIF3F](https://sugi.bio/atlas/gene/EIF3F/) |
| Protein change (HGVS p.) | p.Pro7= |
| Coding change (HGVS c.) | c.21A>G |
| MANE Select transcript | [NM_003754](https://www.ncbi.nlm.nih.gov/nuccore/NM_003754) |
| dbSNP | [rs148453570](https://www.ncbi.nlm.nih.gov/snp/rs148453570/) |
| Variant type | single nucleotide variant |
| Location | chr11:7987373-7987373 (GRCh38) |
| ClinVar | [VCV2498504](https://www.ncbi.nlm.nih.gov/clinvar/variation/2498504/) |

**All HGVS expressions:** `NC_000011.10:g.7987373A>G`, `NC_000011.9:g.8008920A>G`, `NG_121781.1:g.439A>G`, `NM_003754.2:c.21A>G`, `NM_003754.3:c.21A>G`

## 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 **donor gain** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.369, GERP -2.62 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 3.037**. 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 **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.21**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.21**.
- Pangolin: Δ**0.26** (gain), gain 0.26 / loss 0.00. 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 **0.13%** (nfe) · FAF95 0.125% · FAF99 0.123% · 1,537/1,178,022 in the highest group · 1,908/1,596,814 alleles overall — rare (popmax 0.13%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.607% | 165 |
| Remaining individuals (not grpmax-eligible) | 0.14% | 716 |
| European (non-Finnish) (grpmax) | 0.13% | 766 |
| Admixed American | 0.114% | 878 |
| Amish (not grpmax-eligible) | 0.11% | 912 |
| African / African-American | 0.0374% | 2,673 |
| Finnish (not grpmax-eligible) | 0.00599% | 16,699 |
| East Asian | 0.00447% | 22,357 |
| South Asian | 0.0033% | 30,259 |

Ashkenazi Jewish 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}

**EIF3F** population constraint: LOEUF 0.46, pLI 0.99419, missense-Z 0.27315. *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):

- **syndromic intellectual disability** — Definitive (AR)

## Protein context {#protein}

Residue **7** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 75.97, 29% of residues very-high.

**29 experimental structure(s)** (PDB): [28ZX](https://www.rcsb.org/structure/28ZX), [28ZY](https://www.rcsb.org/structure/28ZY), [3J8B](https://www.rcsb.org/structure/3J8B), [3J8C](https://www.rcsb.org/structure/3J8C), [6YBD](https://www.rcsb.org/structure/6YBD), [6ZMW](https://www.rcsb.org/structure/6ZMW).

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

*Describes the biological roles of EIF3F (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:** EIF3F's established molecular role includes identical protein binding. p.Pro7= falls in the disordered region.


### Pathways affected {#pathways}

EIF3F participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of a pool of free 40S subunits](https://reactome.org/content/detail/R-HSA-72689) | curated |
| [Formation of the ternary complex, and subsequently, the 43S complex](https://reactome.org/content/detail/R-HSA-72695) | curated |
| [GTP hydrolysis and joining of the 60S ribosomal subunit](https://reactome.org/content/detail/R-HSA-72706) | curated |
| [IFIT antiviral response](https://reactome.org/content/detail/R-HSA-9684482) | curated |
| [L13a-mediated translational silencing of Ceruloplasmin expression](https://reactome.org/content/detail/R-HSA-156827) | curated |
| [Ribosomal scanning and start codon recognition](https://reactome.org/content/detail/R-HSA-72702) | curated |
| [Translation initiation complex formation](https://reactome.org/content/detail/R-HSA-72649) | curated |

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

**Molecular function:** identical protein binding, metal-dependent deubiquitinase activity.

**Biological process:** translational initiation, IRES-dependent viral translational initiation.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-01.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-08-14 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

**Reported phenotype names (ClinVar):** not provided, EIF3F-related disorder, not specified, none provided, AllHighlyPenetrant, EIF3F-related condition.

## Similar variants {#similar}

Related EIF3F variant pages (same residue, condition, or type): [EIF3F p.Pro7Ser](/variant/eif3f-p-pro7ser), [EIF3F p.Phe232Val](/variant/eif3f-p-phe232val), [EIF3F p.Arg306Cys](/variant/eif3f-p-arg306cys), [EIF3F p.Asn260Ser](/variant/eif3f-p-asn260ser), [EIF3F p.Asp292Glu](/variant/eif3f-p-asp292glu), [EIF3F p.Ser267Gly](/variant/eif3f-p-ser267gly), [EIF3F p.Thr14Met](/variant/eif3f-p-thr14met), [EIF3F p.Thr303Ile](/variant/eif3f-p-thr303ile).

### 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 2498504). 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.*