# NM_006494.4(ERF):c.103G>T (p.Glu35Ter)

https://sugi.bio/variant/erf-p-glu35ter

## Summary

**ERF p.Glu35Ter (c.103G>T)** is classified **Pathogenic** in ERF (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-12). Absent from gnomAD v4.1; Associated with Common craniosynostosis syndromes.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ERF gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Common craniosynostosis syndromes.

*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 | [ERF](https://sugi.bio/atlas/gene/ERF/) |
| Protein change (HGVS p.) | p.Glu35Ter |
| Coding change (HGVS c.) | c.103G>T |
| MANE Select transcript | [NM_006494](https://www.ncbi.nlm.nih.gov/nuccore/NM_006494) |
| Variant type | single nucleotide variant |
| Location | chr19:42250485-42250485 (GRCh38) |
| ClinVar | [VCV4082546](https://www.ncbi.nlm.nih.gov/clinvar/variation/4082546/) |

**All HGVS expressions:** `NC_000019.10:g.42250485C>A`, `NC_000019.9:g.42754637C>A`, `NG_042802.1:g.9680G>T`, `NM_001301035.2:c.-123G>T`, `NM_001308402.2:c.-123G>T`, `NM_001312656.2:c.-123G>T`, `NM_001440420.1:c.-123G>T`, `NM_001440421.1:c.-550-543G>T`, `NM_006494.4:c.103G>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 gain** (Δ 0.90) — consistent with the pathogenic call
- Conservation: phyloP 7.595, GERP 1.8, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.443, pLI 0.99787), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 4**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 54.0**. 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 **0.02**, donor loss **0.00**, acceptor gain **0.90**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.90**, donor gain **0.00**.
- Pangolin: Δ**0.68** (gain), gain 0.68 / 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ERF** population constraint: LOEUF 0.443, pLI 0.99787, missense-Z 1.658; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **craniosynostosis 4** — Definitive (AD)

## Protein context {#protein}

Residue **35** lies in a DNA-binding region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 55.46, 16% of residues very-high.

**2 experimental structure(s)** (PDB): [7JSA](https://www.rcsb.org/structure/7JSA), [7JSL](https://www.rcsb.org/structure/7JSL).

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

*Describes the biological roles of ERF (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:** ERF's established molecular role includes DNA-binding transcription repressor activity, RNA polymerase II-specific. p.Glu35Ter falls in a DNA-binding region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | electronic |

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

**Molecular function:** DNA-binding transcription repressor activity, RNA polymerase II-specific, sequence-specific DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-06-12.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub | Pathogenic | criteria provided, single submitter | clinical testing | 2026-06-12 |

## Associated conditions {#conditions}

[Common craniosynostosis syndromes](https://sugi.bio/atlas/disease/common-craniosynostosis-syndromes/).

**Reported phenotype names (ClinVar):** Common craniosynostosis syndromes.

## Similar variants {#similar}

Related ERF variant pages (same residue, condition, or type): [ERF p.Arg207Ter](/variant/erf-p-arg207ter), [ERF p.Arg218Ter](/variant/erf-p-arg218ter), [ERF p.Arg233Ter](/variant/erf-p-arg233ter), [ERF p.Arg86Cys](/variant/erf-p-arg86cys), [ERF p.Gly53Arg](/variant/erf-p-gly53arg), [ERF p.Tyr89Cys](/variant/erf-p-tyr89cys), [ERF p.Met1Leu](/variant/erf-p-met1leu), [ERF p.Ser169Ter](/variant/erf-p-ser169ter).

### 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 4082546). 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.*