# NM_001099274.3(TINF2):c.993A>G (p.Pro331=)

https://sugi.bio/variant/tinf2-p-pro331

## Summary

**TINF2 p.Pro331= (c.993A>G)** is classified **Likely benign** in TINF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-24). Absent from gnomAD v4.1; Associated with dyskeratosis congenita.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TINF2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to dyskeratosis congenita.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 19 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TINF2 is a diagnostic-grade gene on 16 Genomics England panels |

**Commonly reported features of Dyskeratosis congenita** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypermelanotic macule — Very frequent (99-80%)
- Abnormal fingernail morphology — Very frequent (99-80%)
- Thrombocytopenia — Very frequent (99-80%)
- Abnormality of neutrophils — Very frequent (99-80%)
- Anemia — Very frequent (99-80%)
- Oral leukoplakia — Very frequent (99-80%)
- Abnormal blistering of the skin — Very frequent (99-80%)
- Nail dystrophy — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010905/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TINF2](https://sugi.bio/atlas/gene/TINF2/) |
| Protein change (HGVS p.) | p.Pro331= |
| Coding change (HGVS c.) | c.993A>G |
| MANE Select transcript | [NM_001099274](https://www.ncbi.nlm.nih.gov/nuccore/NM_001099274) |
| Variant type | single nucleotide variant |
| Location | chr14:24240487-24240487 (GRCh38) |
| ClinVar | [VCV4827088](https://www.ncbi.nlm.nih.gov/clinvar/variation/4827088/) |

**All HGVS expressions:** `LRG_342:g.7188A>G`, `LRG_342t1:c.993A>G`, `LRG_342t2:c.993A>G`, `NC_000014.8:g.24709693T>C`, `NC_000014.9:g.24240487T>C`, `NG_016650.1:g.7188A>G`, `NG_054634.1:g.13071T>C`, `NM_001099274.3:c.993A>G`, `NM_001363668.2:c.888A>G`, `NM_012461.3:c.993A>G`

## 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 -3.616, GERP -2.1 — fast-evolving / accelerated position
- CADD: **PHRED 4.994**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for TINF2 (426 scored positions, the nearest 10 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- 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}

**TINF2** population constraint: LOEUF 0.688, pLI 0.0010977, missense-Z 1.3762. *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):

- **dyskeratosis congenita, autosomal dominant 3** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 61.42, 28% of residues very-high.

**3 experimental structure(s)** (PDB): [3BQO](https://www.rcsb.org/structure/3BQO), [3BU8](https://www.rcsb.org/structure/3BU8), [5XYF](https://www.rcsb.org/structure/5XYF).

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

*Describes the biological roles of TINF2 (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:** TINF2's established molecular role includes telomeric repeat DNA binding.


### Pathways affected {#pathways}

TINF2 participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cleavage of the damaged purine](https://reactome.org/content/detail/R-HSA-110331) | other |
| [Cleavage of the damaged pyrimidine ](https://reactome.org/content/detail/R-HSA-110329) | other |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | other |
| [Inhibition of DNA recombination at telomere](https://reactome.org/content/detail/R-HSA-9670095) | other |
| [Meiotic synapsis](https://reactome.org/content/detail/R-HSA-1221632) | other |
| [Packaging Of Telomere Ends](https://reactome.org/content/detail/R-HSA-171306) | other |
| [Polymerase switching on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174411) | other |
| [Processive synthesis on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174414) | other |
| [Recognition and association of DNA glycosylase with site containing an affected purine](https://reactome.org/content/detail/R-HSA-110330) | other |
| [Recognition and association of DNA glycosylase with site containing an affected pyrimidine](https://reactome.org/content/detail/R-HSA-110328) | other |
| [Removal of the Flap Intermediate from the C-strand](https://reactome.org/content/detail/R-HSA-174437) | other |
| [Telomere C-strand (Lagging Strand) Synthesis](https://reactome.org/content/detail/R-HSA-174417) | other |
| [Telomere C-strand synthesis initiation](https://reactome.org/content/detail/R-HSA-174430) | other |
| [Telomere Extension By Telomerase](https://reactome.org/content/detail/R-HSA-171319) | other |

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

**Molecular function:** telomeric repeat DNA binding.

**Biological process:** telomere capping, telomere assembly, negative regulation of telomere maintenance via telomerase, negative regulation of epithelial cell proliferation, protein localization to chromosome, telomeric region, regulation of telomere maintenance via telomere lengthening.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-02-24.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-24 |

## Associated conditions {#conditions}

[dyskeratosis congenita](https://sugi.bio/atlas/disease/dyskeratosis-congenita/).

**Reported phenotype names (ClinVar):** Dyskeratosis congenita.

## Similar variants {#similar}

Related TINF2 variant pages (same residue, condition, or type): [TINF2 p.Arg282Cys](/variant/tinf2-p-arg282cys), [TINF2 p.Arg282His](/variant/tinf2-p-arg282his), [TINF2 p.Leu287Pro](/variant/tinf2-p-leu287pro), [TINF2 c.1061+1G>T](/variant/tinf2-c-1061-plus-1g-t), [TINF2 c.1130-1G>T](/variant/tinf2-c-1130-minus-1g-t), [TINF2 p.Ala10Ser](/variant/tinf2-p-ala10ser), [TINF2 p.Ala124Pro](/variant/tinf2-p-ala124pro), [TINF2 p.Ala124Val](/variant/tinf2-p-ala124val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4827088). 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.*