# NM_001284240.2(CCSER2):c.1727G>A (p.Arg576His)

https://sugi.bio/variant/ccser2-p-arg576his

## Summary

**CCSER2 p.Arg576His (c.1727G>A)** is classified **Uncertain significance** in CCSER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: likely benign (0.0882); Very rare (popmax 0.0033%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs370948089 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.0033%, sas)

## For patients & families {#patients}

This is a change in the CCSER2 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 | [CCSER2](https://sugi.bio/atlas/gene/CCSER2/) |
| Protein change (HGVS p.) | p.Arg576His |
| Coding change (HGVS c.) | c.1727G>A |
| MANE Select transcript | [NM_001284240](https://www.ncbi.nlm.nih.gov/nuccore/NM_001284240) |
| dbSNP | [rs370948089](https://www.ncbi.nlm.nih.gov/snp/rs370948089/) |
| Variant type | single nucleotide variant |
| Location | chr10:84425752-84425752 (GRCh38) |
| ClinVar | [VCV2212886](https://www.ncbi.nlm.nih.gov/clinvar/variation/2212886/) |

**All HGVS expressions:** `NC_000010.10:g.86185508G>A`, `NC_000010.11:g.84425752G>A`, `NM_001284240.2:c.1727G>A`, `NM_001284242.2:c.8G>A`, `NM_001284243.2:c.8G>A`, `NM_001351290.2:c.1727G>A`, `NM_001351292.2:c.1727G>A`, `NM_018999.4:c.1727G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0882)
- REVEL 0.195 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.269 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 8.644, GERP 2.78, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.5**. 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 1.00** across the covering region of the MANE Select transcript (84,371,053–84,514,264), spanning 143,211 bp. Chi-square p 0.88. 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 (G>T, Δ0.31 acceptor 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 **0.0033%** (sas) · FAF95 0.00114% · FAF99 0.000971% · 3/90,782 in the highest group · 28/1,459,960 alleles overall — very rare (popmax 0.0033%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00481% | 20,807 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,558 |
| South Asian (grpmax) | 0.0033% | 30,261 |
| European (non-Finnish) | 0.00178% | 56,138 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CCSER2** population constraint: LOEUF 0.589, pLI 0.073697, missense-Z 0.71631. *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 **576** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 48.62, 6% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-17.

**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 | 2025-05-17 |

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

## Similar variants {#similar}

Related CCSER2 variant pages (same residue, condition, or type): [CCSER2 p.Arg576Cys](/variant/ccser2-p-arg576cys), [CCSER2 c.2326-13498G>A](/variant/ccser2-c-2326-minus-13498g-a), [CCSER2 c.2326-13517C>T](/variant/ccser2-c-2326-minus-13517c-t), [CCSER2 c.2326-13535T>G](/variant/ccser2-c-2326-minus-13535t-g), [CCSER2 c.2326-13543G>T](/variant/ccser2-c-2326-minus-13543g-t), [CCSER2 c.2326-13552T>C](/variant/ccser2-c-2326-minus-13552t-c), [CCSER2 c.2326-13556T>C](/variant/ccser2-c-2326-minus-13556t-c), [CCSER2 c.2326-13558C>T](/variant/ccser2-c-2326-minus-13558c-t).

### 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 2212886). 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.*