# NM_178335.3(CCDC50):c.958C>T (p.Leu320Phe)

https://sugi.bio/variant/ccdc50-p-leu320phe

## Summary

**CCDC50 p.Leu320Phe (c.958C>T)** is classified **Uncertain significance** in CCDC50 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). Very rare (popmax 0.00267%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the CCDC50 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [CCDC50](https://sugi.bio/atlas/gene/CCDC50/) |
| Protein change (HGVS p.) | p.Leu320Phe |
| Coding change (HGVS c.) | c.958C>T |
| MANE Select transcript | [NM_178335](https://www.ncbi.nlm.nih.gov/nuccore/NM_178335) |
| Variant type | single nucleotide variant |
| Location | chr3:191375571-191375571 (GRCh38) |
| ClinVar | [VCV3486738](https://www.ncbi.nlm.nih.gov/clinvar/variation/3486738/) |

**All HGVS expressions:** `LRG_1382:g.51487C>T`, `LRG_1382t1:c.958C>T`, `NC_000003.11:g.191093360C>T`, `NC_000003.12:g.191375571C>T`, `NG_008994.1:g.51487C>T`, `NM_174908.4:c.449-4588C>T`, `NM_178335.3:c.958C>T`

## 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 0.209, GERP -1.56 — weakly conserved position
- CADD: **PHRED 3.104**. 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 0.96** across the covering region of the MANE Select transcript (191,329,675–191,391,757), spanning 62,082 bp. Chi-square p 0.39. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.24 donor loss), 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 **0.00267%** (afr) · FAF95 0.000444% · FAF99 0.000166% · 2/74,836 in the highest group · 4/1,612,990 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00267% | 37,418 |
| European (non-Finnish) | 0.00017% | 589,817 |

*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}

**CCDC50** population constraint: LOEUF 0.933, pLI 4.6044e-11, missense-Z 0.54055. *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** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.90, 47% of residues very-high.

**1 experimental structure(s)** (PDB): [6LAN](https://www.rcsb.org/structure/6LAN).

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

*Describes the biological roles of CCDC50 (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:** CCDC50's established molecular role includes ubiquitin protein ligase binding.


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

**Molecular function:** ubiquitin protein ligase binding.

**Biological process:** sensory perception of sound.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-28 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CCDC50 variant pages (same residue, condition, or type): [CCDC50 p.Leu320Pro](/variant/ccdc50-p-leu320pro), [CCDC50 p.Ala453Val](/variant/ccdc50-p-ala453val), [CCDC50 p.Arg138Pro](/variant/ccdc50-p-arg138pro), [CCDC50 p.Arg227Gln](/variant/ccdc50-p-arg227gln), [CCDC50 p.Arg227Trp](/variant/ccdc50-p-arg227trp), [CCDC50 p.Arg270Ter](/variant/ccdc50-p-arg270ter), [CCDC50 p.Arg274Ter](/variant/ccdc50-p-arg274ter), [CCDC50 p.Arg305Thr](/variant/ccdc50-p-arg305thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3486738). 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.*