# NM_001764.3(CD1B):c.791G>C (p.Arg264Pro)

https://sugi.bio/variant/cd1b-p-arg264pro

## Summary

**CD1B p.Arg264Pro (c.791G>C)** is classified **Uncertain significance** in CD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-25). AlphaMissense: likely pathogenic (0.6288); Very rare (popmax 8.47e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the CD1B 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 | [CD1B](https://sugi.bio/atlas/gene/CD1B/) |
| Protein change (HGVS p.) | p.Arg264Pro |
| Coding change (HGVS c.) | c.791G>C |
| MANE Select transcript | [NM_001764](https://www.ncbi.nlm.nih.gov/nuccore/NM_001764) |
| Variant type | single nucleotide variant |
| Location | chr1:158329465-158329465 (GRCh38) |
| ClinVar | [VCV3829421](https://www.ncbi.nlm.nih.gov/clinvar/variation/3829421/) |

**All HGVS expressions:** `NC_000001.10:g.158299255C>G`, `NC_000001.11:g.158329465C>G`, `NM_001764.3:c.791G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6288)
- REVEL 0.247 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -10.175 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP -7.025, GERP -2.14 — fast-evolving / accelerated position
- CADD: **PHRED 21.9**. 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 1.23** across the covering region of the MANE Select transcript (158,328,239–158,331,423), spanning 3,184 bp. Chi-square p 5.6e-06. 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, Δ0.29 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 **8.47e-05%** (nfe) · 1/1,180,018 in the highest group · 1/1,614,146 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**CD1B** population constraint: LOEUF 1.334, pLI 1.2319e-15, missense-Z -1.2773. *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 **264** lies in a β-strand; the ig-like domain.

AlphaFold model confidence (whole protein): pLDDT 91.00, 83% of residues very-high.

**28 experimental structure(s)** (PDB): [1GZP](https://www.rcsb.org/structure/1GZP), [1GZQ](https://www.rcsb.org/structure/1GZQ), [1UQS](https://www.rcsb.org/structure/1UQS), [2H26](https://www.rcsb.org/structure/2H26), [3OV6](https://www.rcsb.org/structure/3OV6), [3T8X](https://www.rcsb.org/structure/3T8X).

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

*Describes the biological roles of CD1B (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.*


### Pathways affected {#pathways}

CD1B 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 |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-25.

**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 | 2024-12-25 |

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

## Similar variants {#similar}

Related CD1B variant pages (same residue, condition, or type): [CD1B p.Arg264Gln](/variant/cd1b-p-arg264gln), [CD1B p.Gly104Ser](/variant/cd1b-p-gly104ser), [CD1B p.Gly247Ser](/variant/cd1b-p-gly247ser), [CD1B p.Phe76=](/variant/cd1b-p-phe76), [CD1C p.Arg283Thr](/variant/cd1c-p-arg283thr), [CD1C p.Gln23=](/variant/cd1c-p-gln23), [CD1C p.Phe300Ser](/variant/cd1c-p-phe300ser), [CD1C p.Val282Leu](/variant/cd1c-p-val282leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 3829421). 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.*