# NM_001386993.1(CTCFL):c.516C>T (p.Ser172=)

https://sugi.bio/variant/ctcfl-p-ser172

## Summary

**CTCFL p.Ser172= (c.516C>T)** is classified **Benign** in CTCFL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-05-18). Common (popmax 5.82%, afr) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs11907063 · 2 submitters · common (popmax 5.82%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CTCFL gene that is classified as benign — not considered disease-causing, submitted by 2 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 | [CTCFL](https://sugi.bio/atlas/gene/CTCFL/) |
| Protein change (HGVS p.) | p.Ser172= |
| Coding change (HGVS c.) | c.516C>T |
| MANE Select transcript | [NM_001386993](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386993) |
| dbSNP | [rs11907063](https://www.ncbi.nlm.nih.gov/snp/rs11907063/) |
| Variant type | single nucleotide variant |
| Location | chr20:57523690-57523690 (GRCh38) |
| ClinVar | [VCV781569](https://www.ncbi.nlm.nih.gov/clinvar/variation/781569/) |

**All HGVS expressions:** `NC_000020.10:g.56098746G>A`, `NC_000020.11:g.57523690G>A`, `NM_001269040.2:c.516C>T`, `NM_001269041.2:c.516C>T`, `NM_001269042.2:c.516C>T`, `NM_001269043.2:c.516C>T`, `NM_001269044.3:c.516C>T`, `NM_001269045.2:c.516C>T`, `NM_001269046.2:c.516C>T`, `NM_001269047.2:c.516C>T`, `NM_001269048.3:c.516C>T`, `NM_001269049.2:c.-72-412C>T`, `NM_001269050.3:c.-72-412C>T`, `NM_001269051.2:c.516C>T`, `NM_001269052.3:c.516C>T`, `NM_001269054.2:c.-33+1338C>T`, `NM_001269055.3:c.-33+1338C>T`, `NM_001386993.1:c.516C>T`, `NM_001386994.1:c.516C>T`, `NM_001386995.1:c.516C>T`, `NM_001386996.1:c.516C>T`, `NM_001386997.1:c.516C>T`, `NM_080618.4:c.516C>T`, `NR_072975.3:n.1008C>T`, `NR_170377.1:n.1008C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 5.82%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 0.63) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.334, GERP 1.27, phastCons 0.584 — highly conserved position (PP3-type support)
- CADD: **PHRED 17.13**. 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 **0.40**, acceptor gain **0.00**, donor gain **0.63**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.40**, acceptor gain **0.00**, donor gain **0.63**.
- Pangolin: Δ**0.59** (gain), gain 0.59 / loss 0.36. 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 **5.82%** (afr) · FAF95 5.68% · FAF99 5.62% · 4,368/75,034 in the highest group · 7,557/1,613,484 alleles overall — common (popmax 5.82%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 5.82% | 17 |
| Amish (not grpmax-eligible) | 3.29% | 30 |
| South Asian | 2.22% | 45 |
| Remaining individuals (not grpmax-eligible) | 0.642% | 156 |
| Admixed American | 0.623% | 160 |
| Middle Eastern | 0.363% | 276 |
| Finnish (not grpmax-eligible) | 0.178% | 561 |
| East Asian | 0.103% | 976 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.101% | 987 |
| European (non-Finnish) | 0.0125% | 7,973 |

*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}

**CTCFL** population constraint: LOEUF 0.669, pLI 8.2655e-05, missense-Z 1.1139. *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 55.75, 15% of residues very-high.

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

*Describes the biological roles of CTCFL (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:** CTCFL's established molecular role includes transcription cis-regulatory region binding.


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

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA binding, sequence-specific DNA binding.

**Biological process:** positive regulation of gene expression, transcription initiation-coupled chromatin remodeling, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II, establishment of protein localization to chromatin.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-05-18.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-05-18 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related CTCFL variant pages (same residue, condition, or type): [CTCFL p.Val652Met](/variant/ctcfl-p-val652met), [CTCFL p.Ala155Ser](/variant/ctcfl-p-ala155ser), [CTCFL p.Ala155Thr](/variant/ctcfl-p-ala155thr), [CTCFL p.Ala253Thr](/variant/ctcfl-p-ala253thr), [CTCFL p.Ala321Thr](/variant/ctcfl-p-ala321thr), [CTCFL p.Ala434Thr](/variant/ctcfl-p-ala434thr), [CTCFL p.Ala438Thr](/variant/ctcfl-p-ala438thr), [CTCFL p.Ala494Val](/variant/ctcfl-p-ala494val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 781569). 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.*