# NM_001008708.4(CHAC2):c.97T>C (p.Trp33Arg)

https://sugi.bio/variant/chac2-p-trp33arg

## Summary

**CHAC2 p.Trp33Arg (c.97T>C)** is classified **Uncertain significance** in CHAC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely pathogenic (0.987); Ultra-rare (popmax 0.0464%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs201804249 · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0464%, nfe)

## For patients & families {#patients}

This is a change in the CHAC2 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 | [CHAC2](https://sugi.bio/atlas/gene/CHAC2/) |
| Protein change (HGVS p.) | p.Trp33Arg |
| Coding change (HGVS c.) | c.97T>C |
| MANE Select transcript | [NM_016115](https://www.ncbi.nlm.nih.gov/nuccore/NM_016115) (variant reported on NM_001008708) |
| dbSNP | [rs201804249](https://www.ncbi.nlm.nih.gov/snp/rs201804249/) |
| Variant type | single nucleotide variant |
| Location | chr2:53767983-53767983 (GRCh38) |
| ClinVar | [VCV2267051](https://www.ncbi.nlm.nih.gov/clinvar/variation/2267051/) |

**All HGVS expressions:** `NC_000002.11:g.53995120T>C`, `NC_000002.12:g.53767983T>C`, `NG_166754.1:g.308T>C`, `NM_001008708.4:c.97T>C`, `NM_001164165.2:c.102-2398A>G`, `NM_001201965.2:c.-23-17042A>G`, `NM_001346127.1:c.-77T>C`, `NM_016115.5:c.-13-2398A>G`, `NM_145863.3:c.-23-17042A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.987)
- REVEL 0.556 (indeterminate)
- SaProt LLR -15.014 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 7.827, GERP 2.8, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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 1.21** across the covering region of the MANE Select transcript (53,767,887–53,774,522), spanning 6,635 bp. Chi-square p 0.0017. 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 **0.0464%** (nfe) · FAF95 0.0431% · FAF99 0.0418% · 547/1,179,862 in the highest group · 607/1,613,788 alleles overall — ultra-rare (popmax 0.0464%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.088% | 1,136 |
| European (non-Finnish) (grpmax) | 0.0464% | 2,157 |
| African / African-American | 0.00534% | 18,733 |
| Admixed American | 0.00167% | 60,000 |

Remaining individuals 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-20.

**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 | 2024-05-20 |

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

### 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 2267051). 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.*