# NM_006536.7(CLCA2):c.2039C>T (p.Ala680Val)

https://sugi.bio/variant/clca2-p-ala680val

## Summary

**CLCA2 p.Ala680Val (c.2039C>T)** is classified **Uncertain significance** in CLCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-24). AlphaMissense: likely benign (0.081); No allele count reported in gnomAD v4.1 (AN 1,612,840).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2524446048 · 1 submitter · AlphaMissense likely benign · no allele count reported in gnomAD v4.1 (AN 1,612,840)

## For patients & families {#patients}

This is a change in the CLCA2 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 | [CLCA2](https://sugi.bio/atlas/gene/CLCA2/) |
| Protein change (HGVS p.) | p.Ala680Val |
| Coding change (HGVS c.) | c.2039C>T |
| MANE Select transcript | [NM_006536](https://www.ncbi.nlm.nih.gov/nuccore/NM_006536) |
| dbSNP | [rs2524446048](https://www.ncbi.nlm.nih.gov/snp/rs2524446048/) |
| Variant type | single nucleotide variant |
| Location | chr1:86450617-86450617 (GRCh38) |
| ClinVar | [VCV2297314](https://www.ncbi.nlm.nih.gov/clinvar/variation/2297314/) |

**All HGVS expressions:** `NC_000001.10:g.86916300C>T`, `NC_000001.11:g.86450617C>T`, `NM_006536.7:c.2039C>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** (0.081)
- REVEL 0.065 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.28 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.292, GERP -2.7, phastCons 0.998 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.9**. 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 0.97** across the covering region of the MANE Select transcript (86,424,248–86,455,524), spanning 31,276 bp. Chi-square p 0.29. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.08**, donor gain **0.23**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.08**, donor gain **0.23**.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,612,840)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CLCA2** population constraint: LOEUF 1.144, pLI 1.0624e-21, missense-Z 0.93036. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.87, 65% of residues very-high.

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

*Describes the biological roles of CLCA2 (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}

CLCA2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-24.

**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 | 2022-06-24 |

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

## Similar variants {#similar}

Related CLCA2 variant pages (same residue, condition, or type): [CLCA2 p.Leu169Phe](/variant/clca2-p-leu169phe), [CLCA2 p.Gln842=](/variant/clca2-p-gln842), [CLCA2 p.Thr845=](/variant/clca2-p-thr845), [CLCA2 p.Tyr155=](/variant/clca2-p-tyr155), [CLCA2 c.475+2T>A](/variant/clca2-c-475-plus-2t-a), [CLCA2 p.Ala109Val](/variant/clca2-p-ala109val), [CLCA2 p.Ala238Val](/variant/clca2-p-ala238val), [CLCA2 p.Ala262Thr](/variant/clca2-p-ala262thr).

### 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 2297314). 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.*