# NM_017827.4(SARS2):c.696C>T (p.Arg232=)

https://sugi.bio/variant/sars2-p-arg232

## Summary

**SARS2 p.Arg232= (c.696C>T)** is classified **Benign/Likely benign** in SARS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-14). Rare (popmax 0.301%, afr); Associated with hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs35389151 · 5 submitters · 1 linked condition · rare (popmax 0.301%, afr)

## For patients & families {#patients}

This is a change in the SARS2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | SARS2 is a diagnostic-grade gene on 14 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017569/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SARS2](https://sugi.bio/atlas/gene/SARS2/) |
| Protein change (HGVS p.) | p.Arg232= |
| Coding change (HGVS c.) | c.696C>T |
| MANE Select transcript | [NM_017827](https://www.ncbi.nlm.nih.gov/nuccore/NM_017827) |
| dbSNP | [rs35389151](https://www.ncbi.nlm.nih.gov/snp/rs35389151/) |
| Variant type | single nucleotide variant |
| Location | chr19:38919825-38919825 (GRCh38) |
| ClinVar | [VCV380990](https://www.ncbi.nlm.nih.gov/clinvar/variation/380990/) |

**All HGVS expressions:** `NC_000019.10:g.38919825G>A`, `NC_000019.9:g.39410465G>A`, `NG_031865.1:g.16072C>T`, `NM_001145901.2:c.702C>T`, `NM_017827.4:c.696C>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 -20, GERP -3.45 — fast-evolving / accelerated position
- CADD: **PHRED 0.133**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.301%** (afr) · FAF95 0.269% · FAF99 0.257% · 226/75,036 in the highest group · 987/1,614,156 alleles overall — rare (popmax 0.301%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.301% | 332 |
| Remaining individuals (not grpmax-eligible) | 0.0784% | 1,276 |
| European (non-Finnish) | 0.0567% | 1,764 |
| Admixed American | 0.05% | 2,001 |
| Middle Eastern | 0.033% | 3,031 |
| East Asian | 0.0201% | 4,987 |
| South Asian | 0.0022% | 45,543 |

*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}

**SARS2** population constraint: LOEUF 1.02, pLI 9.4058e-16, missense-Z 0.43334. *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):

- **mitochondrial disease** — Moderate (AR)

## Protein context {#protein}

Residue **232** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 90.58, 84% of residues very-high.

**6 experimental structure(s)** (PDB): [7TZB](https://www.rcsb.org/structure/7TZB), [7U2A](https://www.rcsb.org/structure/7U2A), [7U2B](https://www.rcsb.org/structure/7U2B), [7YDF](https://www.rcsb.org/structure/7YDF), [7YDG](https://www.rcsb.org/structure/7YDG), [8FFY](https://www.rcsb.org/structure/8FFY).

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

*Describes the biological roles of SARS2 (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:** SARS2's established molecular role includes RNA binding.


### Pathways affected {#pathways}

SARS2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial tRNA aminoacylation](https://reactome.org/content/detail/R-HSA-379726) | curated |

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

**Molecular function:** RNA binding.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-14.

**Submitter consensus:** conflicting (4 Likely benign, 1 Benign).

**Submission history:** 5 submissions (2020–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-09-15 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-12-17 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-14 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-10-01 |

## Associated conditions {#conditions}

[hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome](https://sugi.bio/atlas/disease/hyperuricemia-pulmonary-hypertension-renal-failure-alkalosis-syndrome/).

**Reported phenotype names (ClinVar):** Hyperuricemia, pulmonary hypertension, renal failure, alkalosis syndrome, not provided, none provided, HUPRA SYNDROME, HYPERURICEMIA, PULMONARY HYPERTENSION, RENAL FAILURE, AND ALKALOSIS SYNDROME.

## Similar variants {#similar}

Related SARS2 variant pages (same residue, condition, or type): [SARS2 p.Arg232Cys](/variant/sars2-p-arg232cys), [SARS2 p.Arg232His](/variant/sars2-p-arg232his), [SARS2 c.759+4T>C](/variant/sars2-c-759-plus-4t-c), [SARS2 c.-5C>A](/variant/sars2-c-minus-5c-a), [SARS2 p.Ala167Val](/variant/sars2-p-ala167val), [SARS2 p.Ala463Val](/variant/sars2-p-ala463val), [SARS2 p.Ala516Ser](/variant/sars2-p-ala516ser), [SARS2 p.Ala73Pro](/variant/sars2-p-ala73pro).

### 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 2026-07-14); 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 380990). 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.*