# NM_005422.4(TECTA):c.260T>G (p.Phe87Cys)

https://sugi.bio/variant/tecta-p-phe87cys

## Summary

**TECTA p.Phe87Cys (c.260T>G)** is classified **Uncertain significance** in TECTA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-01). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with autosomal dominant nonsyndromic hearing loss 12.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2496891408 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TECTA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to autosomal dominant nonsyndromic hearing loss 12.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018107/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TECTA](https://sugi.bio/atlas/gene/TECTA/) |
| Protein change (HGVS p.) | p.Phe87Cys |
| Coding change (HGVS c.) | c.260T>G |
| MANE Select transcript | [NM_005422](https://www.ncbi.nlm.nih.gov/nuccore/NM_005422) |
| dbSNP | [rs2496891408](https://www.ncbi.nlm.nih.gov/snp/rs2496891408/) |
| Variant type | single nucleotide variant |
| Location | chr11:121109272-121109272 (GRCh38) |
| ClinVar | [VCV3248562](https://www.ncbi.nlm.nih.gov/clinvar/variation/3248562/) |

**All HGVS expressions:** `NC_000011.10:g.121109272T>G`, `NC_000011.9:g.120979981T>G`, `NG_011633.1:g.11607T>G`, `NM_001378761.1:c.1217T>G`, `NM_005422.4:c.260T>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9987)
- REVEL 0.84 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.213 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor loss** (Δ 0.34) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.885, GERP 1.47, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in TECTA (of 12,760 modeled).
- CADD: **PHRED 27.4**. 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 0.93** across the covering region of the MANE Select transcript (121,102,666–121,168,849), spanning 66,183 bp. Chi-square p 0.00019. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.34**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**. Largest is acceptor loss, 12 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.02**, 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: **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}

**TECTA** population constraint: LOEUF 0.661, pLI 1.9954e-20, missense-Z 2.4637. *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):

- **nonsyndromic genetic hearing loss** — Definitive (AR)
- **nonsyndromic genetic hearing loss** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 77.64, 19% of residues very-high.

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

*Describes the biological roles of TECTA (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}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Post-translational modification: synthesis of GPI-anchored proteins](https://reactome.org/content/detail/R-HSA-163125) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Goettingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-01 |

## Associated conditions {#conditions}

[autosomal dominant nonsyndromic hearing loss 12](https://sugi.bio/atlas/disease/autosomal-dominant-nonsyndromic-hearing-loss-12/).

**Reported phenotype names (ClinVar):** Autosomal dominant nonsyndromic hearing loss 12, DEAFNESS, AUTOSOMAL DOMINANT 8.

## Similar variants {#similar}

Related TECTA variant pages (same residue, condition, or type): [TECTA p.Arg371Gly](/variant/tecta-p-arg371gly), [TECTA c.4690-1G>A](/variant/tecta-c-4690-minus-1g-a), [TECTA p.Ala567Thr](/variant/tecta-p-ala567thr), [TECTA p.Arg284Cys](/variant/tecta-p-arg284cys), [TECTA p.Arg474Cys](/variant/tecta-p-arg474cys), [TECTA p.Cys1072=](/variant/tecta-p-cys1072), [TECTA p.Cys1402Ser](/variant/tecta-p-cys1402ser), [TECTA p.Cys294Arg](/variant/tecta-p-cys294arg).

### 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 3248562). 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.*