# NM_016111.4(TELO2):c.1929G>A (p.Pro643=)

https://sugi.bio/variant/telo2-p-pro643

## Summary

**TELO2 p.Pro643= (c.1929G>A)** is classified **Likely benign** in TELO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). Very rare (popmax 0.00669%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs778884447 · 1 submitter · very rare (popmax 0.00669%, eas)

## For patients & families {#patients}

This is a change in the TELO2 gene that is classified as likely benign — not considered disease-causing, 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 | [TELO2](https://sugi.bio/atlas/gene/TELO2/) |
| Protein change (HGVS p.) | p.Pro643= |
| Coding change (HGVS c.) | c.1929G>A |
| MANE Select transcript | [NM_016111](https://www.ncbi.nlm.nih.gov/nuccore/NM_016111) |
| dbSNP | [rs778884447](https://www.ncbi.nlm.nih.gov/snp/rs778884447/) |
| Variant type | single nucleotide variant |
| Location | chr16:1505496-1505496 (GRCh38) |
| ClinVar | [VCV1898256](https://www.ncbi.nlm.nih.gov/clinvar/variation/1898256/) |

**All HGVS expressions:** `NC_000016.10:g.1505496G>A`, `NC_000016.9:g.1555497G>A`, `NG_050910.1:g.17153G>A`, `NM_001351846.2:c.1929G>A`, `NM_016111.4:c.1929G>A`

## Computational & population evidence {#evidence}

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

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 0.124, GERP -1.56 — weakly conserved position
- CADD: **PHRED 4.688**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.27 acceptor 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 (gnomAD v4.1): grpmax **0.00669%** (eas) · FAF95 0.00177% · FAF99 0.000891% · 3/44,872 in the highest group · 18/1,613,108 alleles overall — very rare (popmax 0.00669%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00669% | 14,957 |
| South Asian | 0.00329% | 30,363 |
| European (non-Finnish) | 0.00102% | 98,333 |

*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}

**TELO2** population constraint: LOEUF 1.03, pLI 9.4151e-21, missense-Z -0.88114. *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):

- **TELO2-related intellectual disability-neurodevelopmental disorder** — Definitive (AR)

## Protein context {#protein}

Residue **643** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 84.74, 63% of residues very-high.

**4 experimental structure(s)** (PDB): [4PSI](https://www.rcsb.org/structure/4PSI), [7F4U](https://www.rcsb.org/structure/7F4U), [7OLE](https://www.rcsb.org/structure/7OLE), [9WJS](https://www.rcsb.org/structure/9WJS).

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

*Describes the biological roles of TELO2 (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:** TELO2's established molecular role includes kinase binding. p.Pro643= falls in the disordered region.


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

**Molecular function:** kinase binding, protein kinase binding, protein-containing complex binding, Hsp90 protein binding, protein-containing complex stabilizing activity.

**Biological process:** protein stabilization.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-26.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-26 |

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

## Similar variants {#similar}

Related TELO2 variant pages (same residue, condition, or type): [TELO2 c.2034+2T>C](/variant/telo2-c-2034-plus-2t-c), [TELO2 c.2291+1G>C](/variant/telo2-c-2291-plus-1g-c), [TELO2 p.Arg403Ter](/variant/telo2-p-arg403ter), [TELO2 p.Arg609His](/variant/telo2-p-arg609his), [TELO2 p.Cys367Phe](/variant/telo2-p-cys367phe), [TELO2 c.830+5G>T](/variant/telo2-c-830-plus-5g-t), [TELO2 p.Ala198Val](/variant/telo2-p-ala198val), [TELO2 p.Ala323Pro](/variant/telo2-p-ala323pro).

### 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 1898256). 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.*