# NM_004056.6(CA8):c.298T>C (p.Ser100Pro)

https://sugi.bio/variant/ca8-p-ser100pro

## Summary

**CA8 p.Ser100Pro (c.298T>C)** is classified **Pathogenic** in CA8 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2009-05-01). AlphaMissense: likely pathogenic (0.9046); Ultra-rare (popmax 0.0165%, mid); Associated with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs267606695 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the CA8 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Neonatal |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Diagnostic panels | CA8 is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Dysequilibrium syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intellectual disability — Very frequent (99-80%)
- Ataxia — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Hyperreflexia — Very frequent (99-80%)
- Strabismus — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Skeletal muscle atrophy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015634/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CA8](https://sugi.bio/atlas/gene/CA8/) |
| Protein change (HGVS p.) | p.Ser100Pro |
| Coding change (HGVS c.) | c.298T>C |
| MANE Select transcript | [NM_004056](https://www.ncbi.nlm.nih.gov/nuccore/NM_004056) |
| dbSNP | [rs267606695](https://www.ncbi.nlm.nih.gov/snp/rs267606695/) |
| Variant type | single nucleotide variant |
| Location | chr8:60266044-60266044 (GRCh38) |
| ClinVar | [VCV17604](https://www.ncbi.nlm.nih.gov/clinvar/variation/17604/) |

**All HGVS expressions:** `NC_000008.10:g.61178603A>G`, `NC_000008.11:g.60266044A>G`, `NG_023193.2:g.20352T>C`, `NM_001321837.2:c.298T>C`, `NM_001321838.2:c.298T>C`, `NM_001321839.2:c.298T>C`, `NM_004056.6:c.298T>C`, `NR_135821.2:n.551T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9046) — concordant with the pathogenic call
- REVEL 0.485 (indeterminate)
- SaProt LLR -12.128 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 7.564, GERP 1.77, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 22.4**. 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 0.90** across the covering region of the MANE Select transcript (60,266,002–60,281,147), spanning 15,145 bp. Chi-square p 0.24. 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 **0.0165%** (mid) · 1/6,062 in the highest group · 1/1,613,664 alleles overall — ultra-rare (popmax 0.0165%, mid).

*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}

**CA8** population constraint: LOEUF 0.698, pLI 0.23629, missense-Z 1.5581; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, 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):

- **cerebellar ataxia** — Moderate (AR)

## Protein context {#protein}

Residue **100** lies in the alpha-carbonic anhydrase domain; a β-strand; a UniProt-annotated variant site (in scar34; affects protein stability owing to accelerated proteasomal degradation).

AlphaFold model confidence (whole protein): pLDDT 90.51, 85% of residues very-high.

**1 experimental structure(s)** (PDB): [2W2J](https://www.rcsb.org/structure/2W2J).

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2009-05-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2009-05-01 |

## Associated conditions {#conditions}

[cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3](https://sugi.bio/atlas/disease/cerebellar-ataxia-intellectual-disability-and-dysequilibrium-syndrome-3/).

**Reported phenotype names (ClinVar):** Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3, CEREBELLAR ATAXIA AND MENTAL RETARDATION WITH OR WITHOUT QUADRUPEDAL LOCOMOTION 3, SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 34.

## Similar variants {#similar}

Related CA8 variant pages (same residue, condition, or type): [CA8 p.Ser100Leu](/variant/ca8-p-ser100leu), [CA8 c.100+85T>C](/variant/ca8-c-100-plus-85t-c), [CA8 c.-103T>C](/variant/ca8-c-minus-103t-c), [CA8 c.-54A>C](/variant/ca8-c-minus-54a-c), [CA8 p.Glu109=](/variant/ca8-p-glu109), [CA8 p.Arg275Trp](/variant/ca8-p-arg275trp), [CA8 p.Asn84Thr](/variant/ca8-p-asn84thr), [CA8 p.Lys159Ter](/variant/ca8-p-lys159ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 17604). 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.*