# NM_017780.4(CHD7):c.3711C>T (p.Asn1237=)

https://sugi.bio/variant/chd7-p-asn1237

## Summary

**CHD7 p.Asn1237= (c.3711C>T)** is classified **Likely benign** in CHD7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-20). Very rare (popmax 0.00932%, nfe); Associated with CHARGE syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs372498366 · 2 submitters · 1 linked condition · very rare (popmax 0.00932%, nfe)

## For patients & families {#patients}

This is a change in the CHD7 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to CHARGE syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000029/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHD7](https://sugi.bio/atlas/gene/CHD7/) |
| Protein change (HGVS p.) | p.Asn1237= |
| Coding change (HGVS c.) | c.3711C>T |
| MANE Select transcript | [NM_017780](https://www.ncbi.nlm.nih.gov/nuccore/NM_017780) |
| dbSNP | [rs372498366](https://www.ncbi.nlm.nih.gov/snp/rs372498366/) |
| Variant type | single nucleotide variant |
| Location | chr8:60830510-60830510 (GRCh38) |
| ClinVar | [VCV1094671](https://www.ncbi.nlm.nih.gov/clinvar/variation/1094671/) |

**All HGVS expressions:** `LRG_176:g.156731C>T`, `NC_000008.10:g.61743069C>T`, `NC_000008.11:g.60830510C>T`, `NG_007009.1:g.156731C>T`, `NM_001316690.1:c.1717-31719C>T`, `NM_017780.4:c.3711C>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -9.383, GERP -3.94 — fast-evolving / accelerated position
- CADD: **PHRED 1.565**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.58 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 **0.00932%** (nfe) · FAF95 0.00791% · FAF99 0.00736% · 110/1,179,852 in the highest group · 116/1,613,854 alleles overall — very rare (popmax 0.00932%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00932% | 10,726 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,232 |
| East Asian | 0.00223% | 44,900 |
| South Asian | 0.0022% | 45,541 |
| Admixed American | 0.00167% | 60,008 |

*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}

**CHD7** population constraint: LOEUF 0.109, pLI 1, missense-Z 3.9606; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **CHARGE syndrome** — Definitive (AD)

## Protein context {#protein}


**3 experimental structure(s)** (PDB): [2CKC](https://www.rcsb.org/structure/2CKC), [2V0E](https://www.rcsb.org/structure/2V0E), [2V0F](https://www.rcsb.org/structure/2V0F).

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

*Describes the biological roles of CHD7 (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}

CHD7 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CHD6, CHD7, CHD8, CHD9 subfamily](https://reactome.org/content/detail/R-HSA-9943962) | curated |

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

**Biological process:** skeletal system development, in utero embryonic development, heart morphogenesis, central nervous system development, cranial nerve development, T cell differentiation.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-20.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-20 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-09 |

## Associated conditions {#conditions}

[CHARGE syndrome](https://sugi.bio/atlas/disease/charge-syndrome/).

**Reported phenotype names (ClinVar):** CHARGE syndrome, not specified, AllHighlyPenetrant, Hittner Hirsch Kreh syndrome, Coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies, CHARGE association, Hall-Hittner syndrome, CHARGE ASSOCIATION--COLOBOMA, HEART ANOMALY, CHOANAL ATRESIA, RETARDATION, GENITAL AND EAR ANOMALIES.

## Same-residue context {#hotspot}

Residue **1237** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CHD7 p.Asn1237delinsLysArgTrpSerSerTer](/variant/chd7-p-asn1237delinslysargtrpserserter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CHD7 variant pages (same residue, condition, or type): [CHD7 p.Asn1237Ile](/variant/chd7-p-asn1237ile), [CHD7 p.Asn1237delinsLysArgTrpSerSerTer](/variant/chd7-p-asn1237delinslysargtrpserserter), [CHD7 c.2097-2A>G](/variant/chd7-c-2097-minus-2a-g), [CHD7 c.2238+1G>A](/variant/chd7-c-2238-plus-1g-a), [CHD7 c.2377-1G>A](/variant/chd7-c-2377-minus-1g-a), [CHD7 c.2613+1G>A](/variant/chd7-c-2613-plus-1g-a), [CHD7 c.2836-1G>A](/variant/chd7-c-2836-minus-1g-a), [CHD7 c.2836-2A>T](/variant/chd7-c-2836-minus-2a-t).

### 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 2026-07-14); 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 1094671). 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.*