# NM_006494.4(ERF):c.257G>A (p.Arg86His)

https://sugi.bio/variant/erf-p-arg86his

## Summary

**ERF p.Arg86His (c.257G>A)** is classified **Conflicting classifications of pathogenicity** in ERF (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-03-11). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with TWIST1-related craniosynostosis.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs765295141 · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ERF gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to TWIST1-related craniosynostosis.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018045/index) · [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.Arg86His |
| Coding change (HGVS c.) | c.257G>A |
| MANE Select transcript | [NM_006494](https://www.ncbi.nlm.nih.gov/nuccore/NM_006494) |
| dbSNP | [rs765295141](https://www.ncbi.nlm.nih.gov/snp/rs765295141/) |
| Variant type | single nucleotide variant |
| Location | chr19:42250331-42250331 (GRCh38) |
| ClinVar | [VCV946328](https://www.ncbi.nlm.nih.gov/clinvar/variation/946328/) |

**All HGVS expressions:** `NC_000019.10:g.42250331C>T`, `NC_000019.9:g.42754483C>T`, `NG_042802.1:g.9834G>A`, `NM_001301035.2:c.32G>A`, `NM_001308402.2:c.32G>A`, `NM_001312656.2:c.32G>A`, `NM_006494.2:c.257G>A`, `NM_006494.4:c.257G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9993)
- REVEL 0.843 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.149 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor loss** (Δ 0.29) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 7.574, GERP 1.84, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in ERF (of 3,187 modeled).
- CADD: **PHRED 36.0**. 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.*
- Regional missense constraint: **o/e 0.22** across the covering region of the MANE Select transcript (42,249,890–42,250,448), spanning 558 bp — the region is depleted of missense variation. Chi-square p 2.8e-12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.29**, acceptor gain **0.00**, donor gain **0.02**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.29**, acceptor gain **0.00**, donor gain **0.02**.
- Pangolin: Δ**0.48** (loss), gain 0.01 / loss 0.48. 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 **86** lies in a DNA-binding region; a UniProt-annotated variant site (in crs4); 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.Arg86His 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-03-11.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Pathogenic).

**Submission history:** 3 submissions (2024–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-16 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2026-03-11 |

## Associated conditions {#conditions}

[TWIST1-related craniosynostosis](https://sugi.bio/atlas/disease/twist1-related-craniosynostosis/).

**Reported phenotype names (ClinVar):** TWIST1-related craniosynostosis, not provided, Lambdoidal craniosynostosis, CRANIOSYNOSTOSIS 1, none provided.

## Same-residue context {#hotspot}

Residue **86** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ERF p.Arg86Cys](/variant/erf-p-arg86cys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ERF variant pages (same residue, condition, or type): [ERF p.Arg86Cys](/variant/erf-p-arg86cys), [ERF p.Arg183Ter](/variant/erf-p-arg183ter), [ERF p.Arg207Ter](/variant/erf-p-arg207ter), [ERF p.Arg218Ter](/variant/erf-p-arg218ter), [ERF p.Ser24Ter](/variant/erf-p-ser24ter), [ERF p.Arg458Gly](/variant/erf-p-arg458gly), [ERF p.Arg493His](/variant/erf-p-arg493his), [ERF p.Lys401Glu](/variant/erf-p-lys401glu).

### 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 946328). 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.*