# NM_001267.3(CHAD):c.1047C>T (p.Pro349=)

https://sugi.bio/variant/chad-p-pro349

## Summary

**CHAD p.Pro349= (c.1047C>T)** is classified **Benign** in CHAD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-15). Low-frequency (popmax 1.15%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs138527449 · 2 submitters · low-frequency (popmax 1.15%, afr)

## For patients & families {#patients}

This is a change in the CHAD 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 | [CHAD](https://sugi.bio/atlas/gene/CHAD/) |
| Protein change (HGVS p.) | p.Pro349= |
| Coding change (HGVS c.) | c.1047C>T |
| MANE Select transcript | [NM_025149](https://www.ncbi.nlm.nih.gov/nuccore/NM_025149) (variant reported on NM_001267) |
| dbSNP | [rs138527449](https://www.ncbi.nlm.nih.gov/snp/rs138527449/) |
| Variant type | single nucleotide variant |
| Location | chr17:50465331-50465331 (GRCh38) |
| ClinVar | [VCV786655](https://www.ncbi.nlm.nih.gov/clinvar/variation/786655/) |

**All HGVS expressions:** `NC_000017.10:g.48542692G>A`, `NC_000017.11:g.50465331G>A`, `NM_001267.3:c.1047C>T`, `NM_001288968.2:c.1290+1037G>A`, `NM_001288969.2:c.1176+1037G>A`, `NM_001288970.2:c.1086+1037G>A`, `NM_001288971.2:c.735+1037G>A`, `NM_001288972.2:c.735+1037G>A`, `NM_025149.6:c.1215+1037G>A`

## 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 0.871, GERP -1.26, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 6.684**. 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: **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 **1.15%** (afr) · FAF95 1.09% · FAF99 1.06% · 862/75,014 in the highest group · 973/1,614,076 alleles overall — low-frequency (popmax 1.15%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.15% | 87 |
| Admixed American | 0.0833% | 1,200 |
| Remaining individuals (not grpmax-eligible) | 0.0704% | 1,421 |
| Middle Eastern | 0.0495% | 2,021 |
| European (non-Finnish) | 0.0011% | 90,770 |
| South Asian | 0.0011% | 91,066 |

*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 2018-07-15.

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

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-07-15 |
| 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 786655). 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.*