# NM_006494.4(ERF):c.433C>T (p.Pro145Ser)

https://sugi.bio/variant/erf-p-pro145ser

## Summary

**ERF p.Pro145Ser (c.433C>T)** is classified **Uncertain significance** in ERF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-07). AlphaMissense: ambiguous (0.402); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2146950631 · 1 submitter · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ERF 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 | [ERF](https://sugi.bio/atlas/gene/ERF/) |
| Protein change (HGVS p.) | p.Pro145Ser |
| Coding change (HGVS c.) | c.433C>T |
| MANE Select transcript | [NM_006494](https://www.ncbi.nlm.nih.gov/nuccore/NM_006494) |
| dbSNP | [rs2146950631](https://www.ncbi.nlm.nih.gov/snp/rs2146950631/) |
| Variant type | single nucleotide variant |
| Location | chr19:42249679-42249679 (GRCh38) |
| ClinVar | [VCV1313906](https://www.ncbi.nlm.nih.gov/clinvar/variation/1313906/) |

**All HGVS expressions:** `NC_000019.10:g.42249679G>A`, `NC_000019.9:g.42753831G>A`, `NG_042802.1:g.10486C>T`, `NM_001301035.2:c.208C>T`, `NM_001308402.2:c.208C>T`, `NM_001312656.2:c.208C>T`, `NM_006494.4:c.433C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.402) — no call either way
- REVEL 0.175 (moderately benign-leaning)
- SaProt LLR -7.506 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.657, GERP 0.705, phastCons 1 — highly conserved
- CADD: **PHRED 25.9**. 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 0.91** across the covering region of the MANE Select transcript (42,248,468–42,249,889), spanning 1,421 bp. Chi-square p 0.024. 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 **0.00**, acceptor gain **0.24**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**.
- 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 **145** lies in the 'disordered' region.

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.Pro145Ser falls in the disordered 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-01-07.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-01-07 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ERF variant pages (same residue, condition, or type): [ERF p.Arg183Ter](/variant/erf-p-arg183ter), [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.Gln263Ter](/variant/erf-p-gln263ter), [ERF p.Gly53Arg](/variant/erf-p-gly53arg), [ERF p.Ser24Ter](/variant/erf-p-ser24ter).

### 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 1313906). 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.*