# NM_001267.3(CHAD):c.1025C>A (p.Ala342Asp)

https://sugi.bio/variant/chad-p-ala342asp

## Summary

**CHAD p.Ala342Asp (c.1025C>A)** is classified **Likely benign** in CHAD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-01). AlphaMissense: likely pathogenic (0.754); Rare (popmax 0.569%, nfe).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · rare (popmax 0.569%, nfe)

## For patients & families {#patients}

This is a change in the CHAD gene that is classified as likely benign — not considered disease-causing, 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 | [CHAD](https://sugi.bio/atlas/gene/CHAD/) |
| Protein change (HGVS p.) | p.Ala342Asp |
| Coding change (HGVS c.) | c.1025C>A |
| MANE Select transcript | [NM_025149](https://www.ncbi.nlm.nih.gov/nuccore/NM_025149) (variant reported on NM_001267) |
| Variant type | single nucleotide variant |
| Location | chr17:50465353-50465353 (GRCh38) |
| ClinVar | [VCV3770411](https://www.ncbi.nlm.nih.gov/clinvar/variation/3770411/) |

**All HGVS expressions:** `NC_000017.10:g.48542714G>T`, `NC_000017.11:g.50465353G>T`, `NM_001267.3:c.1025C>A`, `NM_001288968.2:c.1290+1059G>T`, `NM_001288969.2:c.1176+1059G>T`, `NM_001288970.2:c.1086+1059G>T`, `NM_001288971.2:c.735+1059G>T`, `NM_001288972.2:c.735+1059G>T`, `NM_025149.6:c.1215+1059G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.754)
- REVEL 0.164 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -7.302 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 11.827, GERP 1.31, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.1**. 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 0.94** across the covering region of the MANE Select transcript (50,465,301–50,468,813), spanning 3,512 bp. Chi-square p 0.21. 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 **0.569%** (nfe) · FAF95 0.557% · FAF99 0.553% · 6,713/1,180,014 in the highest group · 7,772/1,614,094 alleles overall — rare (popmax 0.569%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.861% | 116 |
| European (non-Finnish) (grpmax) | 0.569% | 176 |
| Remaining individuals (not grpmax-eligible) | 0.427% | 234 |
| Amish (not grpmax-eligible) | 0.329% | 304 |
| Middle Eastern | 0.214% | 466 |
| Admixed American | 0.112% | 896 |
| South Asian | 0.0966% | 1,035 |
| African / African-American | 0.0773% | 1,293 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0405% | 2,467 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-01 |

**Reported phenotype names (ClinVar):** not provided, 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 3770411). 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.*