# NM_000574.5(CD55):c.691A>G (p.Ile231Val)

https://sugi.bio/variant/cd55-p-ile231val

## Summary

**CD55 p.Ile231Val (c.691A>G)** is classified **Uncertain significance** in CD55 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-17). AlphaMissense: likely benign (0.1838); Ultra-rare (popmax 0.03%, amr).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs147483928 · 2 submitters · AlphaMissense likely benign · ultra-rare (popmax 0.03%, amr)

## For patients & families {#patients}

This is a change in the CD55 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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 | [CD55](https://sugi.bio/atlas/gene/CD55/) |
| Protein change (HGVS p.) | p.Ile231Val |
| Coding change (HGVS c.) | c.691A>G |
| MANE Select transcript | [NM_000574](https://www.ncbi.nlm.nih.gov/nuccore/NM_000574) |
| dbSNP | [rs147483928](https://www.ncbi.nlm.nih.gov/snp/rs147483928/) |
| Variant type | single nucleotide variant |
| Location | chr1:207331134-207331134 (GRCh38) |
| ClinVar | [VCV1517110](https://www.ncbi.nlm.nih.gov/clinvar/variation/1517110/) |

**All HGVS expressions:** `LRG_127:g.14663A>G`, `NC_000001.10:g.207504479A>G`, `NC_000001.11:g.207331134A>G`, `NG_007465.1:g.14663A>G`, `NM_000574.5:c.691A>G`, `NM_001114752.3:c.691A>G`, `NM_001300902.2:c.691A>G`, `NM_001300903.2:c.691A>G`, `NM_001300904.2:c.691A>G`, `NR_125349.2:n.779A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1838)
- REVEL 0.221 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.828 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.569, GERP -2.06, phastCons 0.002 — weakly conserved position
- CADD: **PHRED 11.48**. 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 0.90** across the covering region of the MANE Select transcript (207,326,827–207,359,607), spanning 32,780 bp. Chi-square p 0.17. 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 **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.03%** (amr) · FAF95 0.0194% · FAF99 0.0164% · 18/59,920 in the highest group · 258/1,613,024 alleles overall — ultra-rare (popmax 0.03%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.03% | 3,329 |
| European (non-Finnish) | 0.0193% | 5,173 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,493 |
| Finnish (not grpmax-eligible) | 0.00625% | 16,001 |
| African / African-American | 0.004% | 25,009 |

*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}

**CD55** population constraint: LOEUF 1.234, pLI 1.1051e-06, missense-Z 0.32192. *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 **231** lies in a disulfide bond; the sushi 4 domain.

AlphaFold model confidence (whole protein): pLDDT 78.99, 66% of residues very-high.

**33 experimental structure(s)** (PDB): [1H03](https://www.rcsb.org/structure/1H03), [1H04](https://www.rcsb.org/structure/1H04), [1H2P](https://www.rcsb.org/structure/1H2P), [1H2Q](https://www.rcsb.org/structure/1H2Q), [1M11](https://www.rcsb.org/structure/1M11), [1NWV](https://www.rcsb.org/structure/1NWV).

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

*Describes the biological roles of CD55 (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:** CD55's established molecular role includes virus receptor activity. p.Ile231Val falls in the sushi 4 domain.


### Pathways affected {#pathways}

CD55 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [Class B/2 (Secretin family receptors)](https://reactome.org/content/detail/R-HSA-373080) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Molecular function:** virus receptor activity, lipid binding.

**Biological process:** positive regulation of T cell cytokine production, positive regulation of cytosolic calcium ion concentration, regulation of complement activation, regulation of lipopolysaccharide-mediated signaling pathway, negative regulation of complement activation, regulation of complement-dependent cytotoxicity.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-07-17.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-16 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-17 |

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

## Similar variants {#similar}

Related CD55 variant pages (same residue, condition, or type): [CD55 c.286+1G>A](/variant/cd55-c-286-plus-1g-a), [CD55 c.286+2T>G](/variant/cd55-c-286-plus-2t-g), [CD55 p.Glu50Ter](/variant/cd55-p-glu50ter), [CD55 p.Trp213Ter](/variant/cd55-p-trp213ter), [CD55 c.1081+1G>C](/variant/cd55-c-1081-plus-1g-c), [CD55 p.Arg221Ser](/variant/cd55-p-arg221ser), [CD55 p.Arg357Cys](/variant/cd55-p-arg357cys), [CD55 p.Arg357His](/variant/cd55-p-arg357his).

### 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 1517110). 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.*