# NM_001162499.2(CAND2):c.1150C>T (p.Arg384Cys)

https://sugi.bio/variant/cand2-p-arg384cys

## Summary

**CAND2 p.Arg384Cys (c.1150C>T)** is classified **Uncertain significance** in CAND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: ambiguous (0.3541); Very rare (popmax 0.00267%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the CAND2 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 | [CAND2](https://sugi.bio/atlas/gene/CAND2/) |
| Protein change (HGVS p.) | p.Arg384Cys |
| Coding change (HGVS c.) | c.1150C>T |
| MANE Select transcript | [NM_001162499](https://www.ncbi.nlm.nih.gov/nuccore/NM_001162499) |
| Variant type | single nucleotide variant |
| Location | chr3:12815284-12815284 (GRCh38) |
| ClinVar | [VCV4648006](https://www.ncbi.nlm.nih.gov/clinvar/variation/4648006/) |

**All HGVS expressions:** `NC_000003.11:g.12856783C>T`, `NC_000003.12:g.12815284C>T`, `NM_001162499.2:c.1150C>T`, `NM_012298.3:c.871C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.3541) — no call either way
- REVEL 0.339 (indeterminate)
- SaProt LLR -8.097 (tolerated)
- Conservation: phyloP 2.967, GERP -4.98, phastCons 0.995 — highly conserved
- CADD: **PHRED 24.3**. 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 0.92** across the covering region of the MANE Select transcript (12,807,350–12,833,979), spanning 26,629 bp. Chi-square p 0.0026. 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, Δ0.31 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 **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000166% · 2/74,954 in the highest group · 9/1,613,860 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00267% | 37,477 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,488 |
| European (non-Finnish) | 0.000508% | 196,676 |

*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}

**CAND2** population constraint: LOEUF 0.815, pLI 3.198e-13, missense-Z 1.1012. *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 **384** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 87.14, 57% of residues very-high.

**2 experimental structure(s)** (PDB): [8VVY](https://www.rcsb.org/structure/8VVY), [9PVH](https://www.rcsb.org/structure/9PVH).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-26.

**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 | 2025-09-26 |

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

## Similar variants {#similar}

Related CAND2 variant pages (same residue, condition, or type): [CAND2 p.Arg768Cys](/variant/cand2-p-arg768cys), [CAND2 p.Arg1028Cys](/variant/cand2-p-arg1028cys), [CAND2 p.Arg987Gln](/variant/cand2-p-arg987gln), [CAND2 p.His709Arg](/variant/cand2-p-his709arg), [CAND2 p.Ser491=](/variant/cand2-p-ser491), [CAND2 p.Ser999=](/variant/cand2-p-ser999), [CAND2 p.Ala1187Val](/variant/cand2-p-ala1187val), [CAND2 p.Ala1215Thr](/variant/cand2-p-ala1215thr).

### 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 4648006). 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.*