# NM_001243212.2(CCER2):c.695A>C (p.Glu232Ala)

https://sugi.bio/variant/ccer2-p-glu232ala

## Summary

**CCER2 p.Glu232Ala (c.695A>C)** is classified **Benign** in CCER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-06). AlphaMissense: likely benign (0.0787); Low-frequency (popmax 1.35%, eas).

**At a glance:** Benign · review: Single submitter · rsID rs369436329 · 1 submitter · AlphaMissense likely benign · low-frequency (popmax 1.35%, eas)

## For patients & families {#patients}

This is a change in the CCER2 gene that is classified as 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 | [CCER2](https://sugi.bio/atlas/gene/CCER2/) |
| Protein change (HGVS p.) | p.Glu232Ala |
| Coding change (HGVS c.) | c.695A>C |
| MANE Select transcript | [NM_001243212](https://www.ncbi.nlm.nih.gov/nuccore/NM_001243212) |
| dbSNP | [rs369436329](https://www.ncbi.nlm.nih.gov/snp/rs369436329/) |
| Variant type | single nucleotide variant |
| Location | chr19:38910579-38910579 (GRCh38) |
| ClinVar | [VCV2859089](https://www.ncbi.nlm.nih.gov/clinvar/variation/2859089/) |

**All HGVS expressions:** `NC_000019.10:g.38910579T>G`, `NC_000019.9:g.39401219T>G`, `NG_029624.1:g.15880T>G`, `NM_001243212.2:c.695A>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0787)
- SaProt LLR -7.716 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated
- Conservation: phyloP -0.627, GERP -1.45 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.516**. 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 1.02** across the covering region of the MANE Select transcript (38,909,239–38,912,158), spanning 2,919 bp. Chi-square p 0.73. 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 (T>C, Δ0.24 donor loss), 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 **1.35%** (eas) · FAF95 1.26% · FAF99 1.22% · 545/40,396 in the highest group · 1,272/1,488,614 alleles overall — low-frequency (popmax 1.35%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 1.35% | 74 |
| South Asian | 0.436% | 230 |
| Remaining individuals (not grpmax-eligible) | 0.16% | 623 |
| European (non-Finnish) | 0.0246% | 4,061 |
| Middle Eastern | 0.0174% | 5,760 |
| Admixed American | 0.0155% | 6,472 |
| Finnish (not grpmax-eligible) | 0.0141% | 7,115 |
| African / African-American | 0.00974% | 10,271 |

*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}

**CCER2** population constraint: LOEUF 1.298, pLI 2.5499e-07, missense-Z -0.93439. *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 **232** lies in a UniProt-annotated variant site (in); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 70.74, 22% of residues very-high.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-06.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2024-10-06 |

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

## Similar variants {#similar}

Related CCER2 variant pages (same residue, condition, or type): [CCER2 p.Glu33Asp](/variant/ccer2-p-glu33asp), [CCER2 c.102+7A>T](/variant/ccer2-c-102-plus-7a-t), [CCER2 p.Ala121Gly](/variant/ccer2-p-ala121gly), [CCER2 p.Ala21Ser](/variant/ccer2-p-ala21ser), [CCER2 p.Arg123Leu](/variant/ccer2-p-arg123leu), [CCER2 p.Arg143Lys](/variant/ccer2-p-arg143lys), [CCER2 p.Arg195His](/variant/ccer2-p-arg195his), [CCER2 p.Glu202Lys](/variant/ccer2-p-glu202lys).

### 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 2859089). 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.*