Is CA8 p.Trp233Cys (c.699G>T) pathogenic?

CA8 p.Trp233Cys (c.699G>T) is classified Uncertain significance in CA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: likely pathogenic (0.9971); Absent from gnomAD v4.1; Associated with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3.

What condition is associated with CA8 p.Trp233Cys (c.699G>T)?

CA8 p.Trp233Cys (c.699G>T) is associated with cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3 (ClinVar).

How common is CA8 p.Trp233Cys (c.699G>T) in the general population?

CA8 p.Trp233Cys (c.699G>T) is absent from gnomAD v4.1 (gnomAD).

How is Dysequilibrium syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CA8 p.Trp233Cys (c.699G>T)?

AlphaMissense predicts likely pathogenic (score 0.9971) — an in-silico prediction, not a clinical call.

CA8 p.Trp233Cys

c.699G>T · VCV4291965

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9971 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3

Computational evidence

Protein change
AlphaMissense	0.9971	likely pathogenic · top 2% in CA8
REVEL	0.9	moderately pathogenic-leaning
SaProt	LLR -10.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 57 kb · p 0.00026 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CA8
Protein: p.Trp233Cys
Coding: c.699G>T
MANE Select: NM_004056
Type: single nucleotide variant
Location: chr8:60222688 (GRCh38)
Gene constraint: LOEUF 0.698 · pLI 0.24 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.51 · 1 PDB
Residue 233: the alpha-carbonic anhydrase domain; a β-strand

Full CA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dysequilibrium syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

CA8 c.100+85T>C Benign ★★ same condition
CA8 c.-103T>C Benign ★★ same condition
CA8 c.-54A>C Benign ★★ same condition
CA8 p.Glu109= Benign ★★ same condition
CA8 p.Arg275Trp Likely pathogenic ★ same condition
CA8 p.Asn84Thr Likely pathogenic ★ same condition
CA8 p.Lys159Ter Likely pathogenic ★ same condition
CA8 c.100+1G>A Likely pathogenic same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ca8-p-trp233cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown