# NM_001371762.2(CD1D):c.65C>G (p.Pro22Arg)

https://sugi.bio/variant/cd1d-p-pro22arg

## Summary

**CD1D p.Pro22Arg (c.65C>G)** is classified **Uncertain significance** in CD1D (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-12). AlphaMissense: likely benign (0.0888); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1648407123 · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CD1D 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 | [CD1D](https://sugi.bio/atlas/gene/CD1D/) |
| Protein change (HGVS p.) | p.Pro22Arg |
| Coding change (HGVS c.) | c.65C>G |
| MANE Select transcript | [NM_001371762](https://www.ncbi.nlm.nih.gov/nuccore/NM_001371762) |
| dbSNP | [rs1648407123](https://www.ncbi.nlm.nih.gov/snp/rs1648407123/) |
| Variant type | single nucleotide variant |
| Location | chr1:158181458-158181458 (GRCh38) |
| ClinVar | [VCV2260709](https://www.ncbi.nlm.nih.gov/clinvar/variation/2260709/) |

**All HGVS expressions:** `NC_000001.10:g.158151248C>G`, `NC_000001.11:g.158181458C>G`, `NM_001319145.2:c.65C>G`, `NM_001371761.1:c.-216-32C>G`, `NM_001371762.2:c.65C>G`, `NM_001371763.1:c.65C>G`, `NM_001766.4:c.65C>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** (0.0888)
- REVEL 0.085 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.822 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -12.782, GERP -3.33 — fast-evolving / accelerated position
- CADD: **PHRED 9.55**. 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 1.05** across the covering region of the MANE Select transcript (158,181,102–158,184,147), spanning 3,045 bp. Chi-square p 0.31. 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 (C>A, Δ0.28 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CD1D** population constraint: LOEUF 1.191, pLI 4.0953e-13, missense-Z -0.13777. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.20, 83% of residues very-high.

**23 experimental structure(s)** (PDB): [1ZT4](https://www.rcsb.org/structure/1ZT4), [2PO6](https://www.rcsb.org/structure/2PO6), [3HUJ](https://www.rcsb.org/structure/3HUJ), [3SDX](https://www.rcsb.org/structure/3SDX), [3TZV](https://www.rcsb.org/structure/3TZV), [3U0P](https://www.rcsb.org/structure/3U0P) — incl. mutant structure 3HUJ.

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

*Describes the biological roles of CD1D (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:** CD1D's established molecular role includes lipid antigen binding.


### Pathways affected {#pathways}

CD1D participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |

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

**Molecular function:** lipid antigen binding, exogenous lipid antigen binding, cell adhesion molecule binding.

**Biological process:** positive regulation of T cell proliferation, antigen processing and presentation, endogenous lipid antigen via MHC class Ib.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-11-12.

**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 | 2021-11-12 |

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

## Similar variants {#similar}

Related CD1D variant pages (same residue, condition, or type): [CD1D p.Thr64Ser](/variant/cd1d-p-thr64ser), [CD1D p.Ala118Ser](/variant/cd1d-p-ala118ser), [CD1D p.Ala11Glu](/variant/cd1d-p-ala11glu), [CD1D p.Ala306Ser](/variant/cd1d-p-ala306ser), [CD1D p.Ala311Val](/variant/cd1d-p-ala311val), [CD1D p.Arg211His](/variant/cd1d-p-arg211his), [CD1D p.Arg24Lys](/variant/cd1d-p-arg24lys), [CD1D p.Arg280Gly](/variant/cd1d-p-arg280gly).

### 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 2260709). 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.*