# NM_016407.5(RTF2):c.67A>G (p.Lys23Glu)

https://sugi.bio/variant/rtf2-p-lys23glu

## Summary

**RTF2 p.Lys23Glu (c.67A>G)** is classified **Uncertain significance** in RTF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-23). AlphaMissense: ambiguous (0.4956); No allele count reported in gnomAD v4.1 (AN 1,578,702).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2515982391 · 1 submitter · AlphaMissense ambiguous · no allele count reported in gnomAD v4.1 (AN 1,578,702)

## For patients & families {#patients}

This is a change in the RTF2 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 | [RTF2](https://sugi.bio/atlas/gene/RTF2/) |
| Protein change (HGVS p.) | p.Lys23Glu |
| Coding change (HGVS c.) | c.67A>G |
| MANE Select transcript | [NM_016407](https://www.ncbi.nlm.nih.gov/nuccore/NM_016407) |
| dbSNP | [rs2515982391](https://www.ncbi.nlm.nih.gov/snp/rs2515982391/) |
| Variant type | single nucleotide variant |
| Location | chr20:56468764-56468764 (GRCh38) |
| ClinVar | [VCV3156844](https://www.ncbi.nlm.nih.gov/clinvar/variation/3156844/) |

**All HGVS expressions:** `NC_000020.10:g.55043820A>G`, `NC_000020.11:g.56468764A>G`, `NM_001283035.2:c.67A>G`, `NM_001283036.2:c.67A>G`, `NM_001283037.2:c.67A>G`, `NM_016407.5:c.67A>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.4956) — no call either way
- REVEL 0.224 (benign-leaning)
- SaProt LLR -12.174 (damaging)
- → **In-silico consensus:** SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate
- Conservation: phyloP 10.995, GERP 2.53, phastCons 1 — highly conserved
- CADD: **PHRED 33.0**. 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 0.82** across the covering region of the MANE Select transcript (56,468,698–56,518,262), spanning 49,564 bp. Chi-square p 0.00043. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.40 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,578,702)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**RTF2** population constraint: LOEUF 0.806, pLI 0.0050684, missense-Z 1.0615. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.24, 28% of residues very-high.

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

*Describes the biological roles of RTF2 (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:** RTF2's established molecular role includes DNA binding.


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

**Molecular function:** DNA binding.

**Biological process:** cellular response to hydroxyurea, regulation of DNA stability.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-23.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-23 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related RTF2 variant pages (same residue, condition, or type): [RTF2 p.Arg118Cys](/variant/rtf2-p-arg118cys), [RTF2 p.Arg147Pro](/variant/rtf2-p-arg147pro), [RTF2 p.Arg46Gln](/variant/rtf2-p-arg46gln), [RTF2 p.Asn87Ser](/variant/rtf2-p-asn87ser), [RTF2 p.Asn96Ser](/variant/rtf2-p-asn96ser), [RTF2 p.Asp25Asn](/variant/rtf2-p-asp25asn), [RTF2 p.Cys135Phe](/variant/rtf2-p-cys135phe), [RTF2 p.Cys140Tyr](/variant/rtf2-p-cys140tyr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 3156844). 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.*