# NM_022092.3(CHTF18):c.760T>C (p.Ser254Pro)

https://sugi.bio/variant/chtf18-p-ser254pro

## Summary

**CHTF18 p.Ser254Pro (c.760T>C)** is classified **Benign** in CHTF18 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-01-30). AlphaMissense: likely benign (0.0613); Low-frequency (popmax 1.38%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs143450560 · 2 submitters · AlphaMissense likely benign · low-frequency (popmax 1.38%, afr)

## For patients & families {#patients}

This is a change in the CHTF18 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 | [CHTF18](https://sugi.bio/atlas/gene/CHTF18/) |
| Protein change (HGVS p.) | p.Ser254Pro |
| Coding change (HGVS c.) | c.760T>C |
| MANE Select transcript | [NM_022092](https://www.ncbi.nlm.nih.gov/nuccore/NM_022092) |
| dbSNP | [rs143450560](https://www.ncbi.nlm.nih.gov/snp/rs143450560/) |
| Variant type | single nucleotide variant |
| Location | chr16:790532-790532 (GRCh38) |
| ClinVar | [VCV724412](https://www.ncbi.nlm.nih.gov/clinvar/variation/724412/) |

**All HGVS expressions:** `NC_000016.10:g.790532T>C`, `NC_000016.9:g.840532T>C`, `NG_047098.1:g.2856A>G`, `NM_022092.3:c.760T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0613)
- REVEL 0.032 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.14 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.32) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.94, GERP -4.13 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.074**. 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 1.43** across the covering region of the MANE Select transcript (788,685–797,972), spanning 9,287 bp. Chi-square p 1.1e-58. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.32**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**. Largest is acceptor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **1.38%** (afr) · FAF95 1.31% · FAF99 1.28% · 1,031/74,640 in the highest group · 1,113/1,600,368 alleles overall — low-frequency (popmax 1.38%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.38% | 72 |
| Remaining individuals (not grpmax-eligible) | 0.0742% | 1,348 |
| Admixed American | 0.0518% | 1,932 |
| Middle Eastern | 0.0166% | 6,032 |
| European (non-Finnish) | 0.000426% | 234,906 |

*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}

**CHTF18** population constraint: LOEUF 1.712, pLI 5.6719e-69, missense-Z -7.3404. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **254** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 64.97, 9% of residues very-high.

**10 experimental structure(s)** (PDB): [8UMT](https://www.rcsb.org/structure/8UMT), [8UMU](https://www.rcsb.org/structure/8UMU), [8UMV](https://www.rcsb.org/structure/8UMV), [8UMW](https://www.rcsb.org/structure/8UMW), [8UMY](https://www.rcsb.org/structure/8UMY), [8UN0](https://www.rcsb.org/structure/8UN0).

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

*Describes the biological roles of CHTF18 (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.*


### Pathways affected {#pathways}

CHTF18 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Polymerase switching on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174411) | curated |

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

**Biological process:** positive regulation of DNA-directed DNA polymerase activity.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-01-30.

**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 | 2018-01-30 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

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

## Similar variants {#similar}

Related CHTF18 variant pages (same residue, condition, or type): [CHTF18 p.Ser254Leu](/variant/chtf18-p-ser254leu), [CHTF18 p.Ala770=](/variant/chtf18-p-ala770), [CHTF18 p.Arg804Cys](/variant/chtf18-p-arg804cys), [CHTF18 p.Asn820=](/variant/chtf18-p-asn820), [CHTF18 p.Asp284Glu](/variant/chtf18-p-asp284glu), [CHTF18 p.Glu233Lys](/variant/chtf18-p-glu233lys), [CHTF18 p.His179=](/variant/chtf18-p-his179), [CHTF18 p.Leu541=](/variant/chtf18-p-leu541).

### 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 724412). 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.*