# NM_001256106.3(CD101):c.2974C>T (p.Arg992Trp)

https://sugi.bio/variant/cd101-p-arg992trp

## Summary

**CD101 p.Arg992Trp (c.2974C>T)** is classified **Benign** in CD101 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0834); Common (popmax 7.17%, afr) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs34248572 · 2 submitters · AlphaMissense likely benign · common (popmax 7.17%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CD101 gene that is classified as benign — not considered disease-causing, 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 | [CD101](https://sugi.bio/atlas/gene/CD101/) |
| Protein change (HGVS p.) | p.Arg992Trp |
| Coding change (HGVS c.) | c.2974C>T |
| dbSNP | [rs34248572](https://www.ncbi.nlm.nih.gov/snp/rs34248572/) |
| Variant type | single nucleotide variant |
| Location | chr1:117034009-117034009 (GRCh38) |
| ClinVar | [VCV780258](https://www.ncbi.nlm.nih.gov/clinvar/variation/780258/) |

**All HGVS expressions:** `NC_000001.10:g.117576631C>T`, `NC_000001.11:g.117034009C>T`, `NM_001256106.3:c.2974C>T`, `NM_001256109.3:c.2974C>T`, `NM_001256111.3:c.2788C>T`, `NM_004258.6:c.2974C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 7.17%, afr) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0834)
- REVEL 0.098 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.855 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.214, GERP -0.497 — weakly conserved position
- CADD: **PHRED 15.91**. 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 0.94** across the covering region of the MANE Select transcript (117,001,818–117,034,098), spanning 32,280 bp. Chi-square p 0.034. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **7.17%** (afr) · FAF95 7.01% · FAF99 6.94% · 5,374/74,952 in the highest group · 6,178/1,614,030 alleles overall — common (popmax 7.17%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 7.17% | 14 |
| Admixed American | 0.538% | 186 |
| Remaining individuals (not grpmax-eligible) | 0.467% | 214 |
| Middle Eastern | 0.231% | 433 |
| South Asian | 0.0318% | 3,141 |
| European (non-Finnish) | 0.012% | 8,310 |
| East Asian | 0.00446% | 22,437 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,002 |

*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.*

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2019-12-31.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2019); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

### 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 780258). 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.*