# NM_001365709.1(CNBD2):c.704T>C (p.Phe235Ser)

https://sugi.bio/variant/cnbd2-p-phe235ser

## Summary

**CNBD2 p.Phe235Ser (c.704T>C)** is classified **Uncertain significance** in CNBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-03). AlphaMissense: ambiguous (0.4984); Very rare (popmax 0.000763%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.000763%, nfe)

## For patients & families {#patients}

This is a change in the CNBD2 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 | [CNBD2](https://sugi.bio/atlas/gene/CNBD2/) |
| Protein change (HGVS p.) | p.Phe235Ser |
| Coding change (HGVS c.) | c.704T>C |
| MANE Select transcript | [NM_001365709](https://www.ncbi.nlm.nih.gov/nuccore/NM_001365709) |
| Variant type | single nucleotide variant |
| Location | chr20:35984766-35984766 (GRCh38) |
| ClinVar | [VCV4230662](https://www.ncbi.nlm.nih.gov/clinvar/variation/4230662/) |

**All HGVS expressions:** `NC_000020.10:g.34572688T>C`, `NC_000020.11:g.35984766T>C`, `NM_001207076.3:c.704T>C`, `NM_001365709.1:c.704T>C`, `NM_080834.4:c.704T>C`, `NR_130714.2:n.720T>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; SaProt calls this damaging; REVEL does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4984) — no call either way
- REVEL 0.228 (benign-leaning)
- SaProt LLR -11.043 (damaging)
- → **In-silico consensus:** SaProt calls this damaging; REVEL does not; AlphaMissense makes no call
- Conservation: phyloP 5.074, GERP 0.694, phastCons 1 — highly conserved
- CADD: **PHRED 24.1**. 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 0.97** across the covering region of the MANE Select transcript (35,968,763–36,030,645), spanning 61,882 bp. Chi-square p 0.4. 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 (T>A, Δ0.98 donor 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 **0.000763%** (nfe) · FAF95 0.000359% · FAF99 0.00026% · 9/1,180,022 in the highest group · 9/1,614,166 alleles overall — very rare (popmax 0.000763%, 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}

**CNBD2** population constraint: LOEUF 1.173, pLI 1.0435e-17, missense-Z 0.75914. *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 **235** lies in a binding site.

AlphaFold model confidence (whole protein): pLDDT 69.79, 20% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-03.

**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 | 2025-07-03 |

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

## Similar variants {#similar}

Related CNBD2 variant pages (same residue, condition, or type): [CNBD2 p.Ala121Thr](/variant/cnbd2-p-ala121thr), [CNBD2 p.Ala566Gly](/variant/cnbd2-p-ala566gly), [CNBD2 p.Ala566Thr](/variant/cnbd2-p-ala566thr), [CNBD2 p.Ala576Thr](/variant/cnbd2-p-ala576thr), [CNBD2 p.Ala88Thr](/variant/cnbd2-p-ala88thr), [CNBD2 p.Arg118Trp](/variant/cnbd2-p-arg118trp), [CNBD2 p.Arg133Cys](/variant/cnbd2-p-arg133cys), [CNBD2 p.Arg133His](/variant/cnbd2-p-arg133his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 4230662). 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.*