# NM_153700.2(STRC):c.4842C>T (p.Phe1614=)

https://sugi.bio/variant/strc-p-phe1614

## Summary

**STRC p.Phe1614= (c.4842C>T)** is classified **Benign** in STRC (ClinVar, Multiple submitters, 9 submitters; last evaluated 2024-11-27). Common (popmax 70.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive nonsyndromic hearing loss 16.

**At a glance:** Benign · review: Multiple submitters · rsID rs3097773 · 9 submitters · 1 linked condition · common (popmax 70.1%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the STRC gene that is classified as benign — not considered disease-causing, submitted by 9 submitters, and is linked to autosomal recessive nonsyndromic hearing loss 16.

*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/0022597/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STRC](https://sugi.bio/atlas/gene/STRC/) |
| Protein change (HGVS p.) | p.Phe1614= |
| Coding change (HGVS c.) | c.4842C>T |
| MANE Select transcript | [NM_153700](https://www.ncbi.nlm.nih.gov/nuccore/NM_153700) |
| dbSNP | [rs3097773](https://www.ncbi.nlm.nih.gov/snp/rs3097773/) |
| Variant type | single nucleotide variant |
| Location | chr15:43600874-43600874 (GRCh38) |
| ClinVar | [VCV177982](https://www.ncbi.nlm.nih.gov/clinvar/variation/177982/) |

**All HGVS expressions:** `NC_000015.10:g.43600874G>A`, `NC_000015.9:g.43893072G>A`, `NG_011636.1:g.22927C>T`, `NM_153700.2:c.4842C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 70.1%, 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 loss** (Δ 0.38) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.285, GERP -1.57, phastCons 0.449 — weakly conserved position
- CADD: **PHRED 14.0**. 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 **0.38**, acceptor gain **0.00**, donor gain **0.12**. Largest is donor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.12**.
  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.*
- Pangolin: Δ**0.38** (loss), gain 0.15 / loss 0.38. 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 **70.1%** (afr) · FAF95 69.6% · FAF99 69.4% · 52,060/74,232 in the highest group · 239,690/1,608,376 alleles overall — common (popmax 70.1%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 70.1% | 1 |
| East Asian | 43% | 2 |
| Admixed American | 21.5% | 5 |
| South Asian | 19.6% | 5 |
| Ashkenazi Jewish (not grpmax-eligible) | 19.2% | 5 |
| Remaining individuals (not grpmax-eligible) | 17.5% | 6 |
| Middle Eastern | 15.7% | 6 |
| Amish (not grpmax-eligible) | 10.7% | 9 |
| European (non-Finnish) | 9.79% | 10 |
| Finnish (not grpmax-eligible) | 7.66% | 13 |

*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}

**STRC** population constraint: LOEUF 0.713, pLI 3.8356e-06, missense-Z 2.7229. *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)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 69.21, 18% of residues very-high.

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

*Describes the biological roles of STRC (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}

STRC participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | other |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | other |

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-11-27.

**Submitter consensus:** unanimous (8/8 Benign).

**Submission history:** 13 submissions (2013–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2013-06-26 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2017-05-09 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2021-05-07 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

## Associated conditions {#conditions}

[autosomal recessive nonsyndromic hearing loss 16](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-16/).

**Reported phenotype names (ClinVar):** Autosomal recessive nonsyndromic hearing loss 16, not specified, Malignant lymphoma, large B-cell, diffuse, Uterine carcinosarcoma, not provided, Colorectal cancer, AllHighlyPenetrant, none provided, DFNB16 Nonsyndromic Hearing Loss and Deafness, DEAFNESS, AUTOSOMAL RECESSIVE 16.

## Similar variants {#similar}

Related STRC variant pages (same residue, condition, or type): [STRC c.4219-1G>A](/variant/strc-c-4219-minus-1g-a), [STRC c.4701+1G>A](/variant/strc-c-4701-plus-1g-a), [STRC p.Arg1073Ter](/variant/strc-p-arg1073ter), [STRC p.Arg1154Ter](/variant/strc-p-arg1154ter), [STRC p.Arg1224Ter](/variant/strc-p-arg1224ter), [STRC p.Arg1338Ter](/variant/strc-p-arg1338ter), [STRC p.Arg1451Ter](/variant/strc-p-arg1451ter), [STRC p.Arg1468Ter](/variant/strc-p-arg1468ter).

### 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 177982). 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.*