# NM_000717.5(CA4):c.510G>A (p.Val170=)

https://sugi.bio/variant/ca4-p-val170

## Summary

**CA4 p.Val170= (c.510G>A)** is classified **Likely benign** in CA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-28). Very rare (popmax 0.0011%, sas).

**At a glance:** Likely benign · review: Single submitter · rsID rs749723077 · 1 submitter · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the CA4 gene that is classified as likely benign — not considered disease-causing, 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 | [CA4](https://sugi.bio/atlas/gene/CA4/) |
| Protein change (HGVS p.) | p.Val170= |
| Coding change (HGVS c.) | c.510G>A |
| MANE Select transcript | [NM_000717](https://www.ncbi.nlm.nih.gov/nuccore/NM_000717) |
| dbSNP | [rs749723077](https://www.ncbi.nlm.nih.gov/snp/rs749723077/) |
| Variant type | single nucleotide variant |
| Location | chr17:60157785-60157785 (GRCh38) |
| ClinVar | [VCV1102816](https://www.ncbi.nlm.nih.gov/clinvar/variation/1102816/) |

**All HGVS expressions:** `NC_000017.10:g.58235146G>A`, `NC_000017.11:g.60157785G>A`, `NG_012050.2:g.12845G>A`, `NM_000717.5:c.510G>A`, `NR_137422.2:n.572G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.66) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.825, GERP 1.66, phastCons 0.999 — highly conserved position (PP3-type support)
- CADD: **PHRED 18.87**. 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 **0.01**, acceptor gain **0.00**, donor gain **0.66**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.66**.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/91,046 in the highest group · 3/1,460,104 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,046 |
| European (non-Finnish) | 0.00017% | 589,244 |

*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}

**CA4** population constraint: LOEUF 0.975, pLI 1.3264e-06, missense-Z 0.13739. *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 **170** lies in a disulfide bond; the alpha-carbonic anhydrase domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 89.86, 81% of residues very-high.

**10 experimental structure(s)** (PDB): [1ZNC](https://www.rcsb.org/structure/1ZNC), [3F7B](https://www.rcsb.org/structure/3F7B), [3F7U](https://www.rcsb.org/structure/3F7U), [3FW3](https://www.rcsb.org/structure/3FW3), [5IPZ](https://www.rcsb.org/structure/5IPZ), [5JN8](https://www.rcsb.org/structure/5JN8).

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

*Describes the biological roles of CA4 (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}

CA4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Erythrocytes take up carbon dioxide and release oxygen](https://reactome.org/content/detail/R-HSA-1237044) | curated |
| [Erythrocytes take up oxygen and release carbon dioxide](https://reactome.org/content/detail/R-HSA-1247673) | curated |
| [Reversible hydration of carbon dioxide](https://reactome.org/content/detail/R-HSA-1475029) | curated |

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

**Biological process:** bicarbonate transport.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-28.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-28 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CA4 variant pages (same residue, condition, or type): [CA4 c.745-9C>G](/variant/ca4-c-745-minus-9c-g), [CA4 p.Ala156Val](/variant/ca4-p-ala156val), [CA4 p.Ala308Ser](/variant/ca4-p-ala308ser), [CA4 p.Arg279Pro](/variant/ca4-p-arg279pro), [CA4 p.Arg50His](/variant/ca4-p-arg50his), [CA4 p.Arg50Ser](/variant/ca4-p-arg50ser), [CA4 p.Asp131Asn](/variant/ca4-p-asp131asn), [CA4 p.Asp206Glu](/variant/ca4-p-asp206glu).

### 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 1102816). 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.*