# NM_199287.3(CCDC137):c.26C>T (p.Ala9Val)

https://sugi.bio/variant/ccdc137-p-ala9val

## Summary

**CCDC137 p.Ala9Val (c.26C>T)** is classified **Uncertain significance** in CCDC137 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.1309); Ultra-rare (popmax 0.0693%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs374543963 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0693%, afr)

## For patients & families {#patients}

This is a change in the CCDC137 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 | [CCDC137](https://sugi.bio/atlas/gene/CCDC137/) |
| Protein change (HGVS p.) | p.Ala9Val |
| Coding change (HGVS c.) | c.26C>T |
| MANE Select transcript | [NM_199287](https://www.ncbi.nlm.nih.gov/nuccore/NM_199287) |
| dbSNP | [rs374543963](https://www.ncbi.nlm.nih.gov/snp/rs374543963/) |
| Variant type | single nucleotide variant |
| Location | chr17:81666792-81666792 (GRCh38) |
| ClinVar | [VCV2514351](https://www.ncbi.nlm.nih.gov/clinvar/variation/2514351/) |

**All HGVS expressions:** `NC_000017.10:g.79633822C>T`, `NC_000017.11:g.81666792C>T`, `NG_009834.2:g.1627G>A`, `NG_138083.1:g.1092C>T`, `NG_138084.1:g.170C>T`, `NM_199287.3:c.26C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1309)
- REVEL 0.18 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.357 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -4.911, GERP -2.4 — fast-evolving / accelerated position
- CADD: **PHRED 1.612**. 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 1.10** across the covering region of the MANE Select transcript (81,666,767–81,672,701), spanning 5,934 bp. Chi-square p 0.06. 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>A, Δ0.21 donor 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 **0.0693%** (afr) · FAF95 0.0535% · FAF99 0.0479% · 47/67,804 in the highest group · 83/1,467,708 alleles overall — ultra-rare (popmax 0.0693%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0693% | 1,443 |
| East Asian | 0.00818% | 12,222 |
| Remaining individuals (not grpmax-eligible) | 0.00718% | 13,934 |
| South Asian | 0.00416% | 24,015 |
| Admixed American | 0.00257% | 38,918 |
| European (non-Finnish) | 0.00224% | 44,600 |

*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}

**CCDC137** population constraint: LOEUF 1.308, pLI 1.0316e-07, missense-Z -1.8238. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **9** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 74.94, 30% of residues very-high.

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

*Describes the biological roles of CCDC137 (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:** CCDC137's established molecular role includes RNA binding. p.Ala9Val falls in the disordered region.


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

**Molecular function:** RNA binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-19.

**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 | 2025-11-19 |

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

## Similar variants {#similar}

Related CCDC137 variant pages (same residue, condition, or type): [CCDC137 p.Ala9Glu](/variant/ccdc137-p-ala9glu), [CCDC137 p.Arg247Cys](/variant/ccdc137-p-arg247cys), [CCDC137 p.Ala144Thr](/variant/ccdc137-p-ala144thr), [CCDC137 p.Ala261Val](/variant/ccdc137-p-ala261val), [CCDC137 p.Ala2Ser](/variant/ccdc137-p-ala2ser), [CCDC137 p.Ala2Val](/variant/ccdc137-p-ala2val), [CCDC137 p.Arg12Ser](/variant/ccdc137-p-arg12ser), [CCDC137 p.Arg146Gln](/variant/ccdc137-p-arg146gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 2514351). 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.*