# NM_017780.4(CHD7):c.1105C>T (p.Pro369Ser)

https://sugi.bio/variant/chd7-p-pro369ser

## Summary

**CHD7 p.Pro369Ser (c.1105C>T)** is classified **Benign** in CHD7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-10). AlphaMissense: likely benign (0.0966); Ultra-rare (popmax 0.0201%, eas); Associated with CHARGE syndrome.

**At a glance:** Benign · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0201%, eas)

## For patients & families {#patients}

This is a change in the CHD7 gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, 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.Pro369Ser |
| Coding change (HGVS c.) | c.1105C>T |
| MANE Select transcript | [NM_017780](https://www.ncbi.nlm.nih.gov/nuccore/NM_017780) |
| Variant type | single nucleotide variant |
| Location | chr8:60742537-60742537 (GRCh38) |
| ClinVar | [VCV4741376](https://www.ncbi.nlm.nih.gov/clinvar/variation/4741376/) |

**All HGVS expressions:** `LRG_176:g.68758C>T`, `LRG_176t1:c.1105C>T`, `NC_000008.10:g.61655096C>T`, `NC_000008.11:g.60742537C>T`, `NG_007009.1:g.68758C>T`, `NM_001316690.1:c.1105C>T`, `NM_017780.4:c.1105C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0966)
- REVEL 0.054 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP 3.09, GERP -0.152, phastCons 1 — highly conserved (differs from AlphaMissense)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 22.9**. 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 0.99** across the covering region of the MANE Select transcript (60,741,433–60,801,550), spanning 60,117 bp. Chi-square p 0.84. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0201%** (eas) · FAF95 0.0104% · FAF99 0.00779% · 9/44,886 in the highest group · 11/1,613,990 alleles overall — ultra-rare (popmax 0.0201%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0201% | 4,987 |
| European (non-Finnish) | 0.00017% | 589,950 |

*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 3/3, triplosensitivity 0/3. *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}

Residue **369** lies in a UniProt-annotated variant site (in).

**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}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-10.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-05-10 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** CHARGE syndrome, Coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies, CHARGE association, Hall-Hittner syndrome, Hittner Hirsch Kreh syndrome, CHARGE ASSOCIATION--COLOBOMA, HEART ANOMALY, CHOANAL ATRESIA, RETARDATION, GENITAL AND EAR ANOMALIES.

## Similar variants {#similar}

Related CHD7 variant pages (same residue, condition, or type): [CHD7 p.Pro369Ala](/variant/chd7-p-pro369ala), [CHD7 p.Pro369=](/variant/chd7-p-pro369), [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 2026-10-14); 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 4741376). 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.*