Is CA4 p.Val233= (c.699C>T) pathogenic?

CA4 p.Val233= (c.699C>T) is classified Conflicting classifications of pathogenicity in CA4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2018-01-12). Very rare (popmax 0.00446%, eas); Associated with retinitis pigmentosa.

What condition is associated with CA4 p.Val233= (c.699C>T)?

CA4 p.Val233= (c.699C>T) is associated with retinitis pigmentosa (ClinVar).

How common is CA4 p.Val233= (c.699C>T) in the general population?

CA4 p.Val233= (c.699C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Retinitis pigmentosa inherited?

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

CA4 p.Val233=

c.699C>T · rs764759588 · VCV728481

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

retinitis pigmentosa

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.95 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.5	GERP -4.2
Overall
CADD	0.442	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,876 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000958% 14/1,461,814 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,438
South Asian	0.0022%	45,535
Admixed American	0.00167%	60,020
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.000678%	147,503

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CA4
Protein: p.Val233=
Coding: c.699C>T
MANE Select: NM_000717
dbSNP: rs764759588
Type: single nucleotide variant
Location: chr17:60158401 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 233: the alpha-carbonic anhydrase domain; a β-strand

Full CA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CA4 p.Val233Leu Uncertain significance ★★ ⚠ same residue
CA4 p.Ile54Met Uncertain significance ★★ ⚠ same condition
CA4 p.Phe70Leu Uncertain significance ★★ ⚠ same condition
CA4 c.-24G>C Benign ★★ same condition
CA4 c.-47C>G Benign ★★ same condition
CA4 p.Arg239Gln Benign ★★ same condition
CA4 p.Asn177Lys Benign/Likely benign ★★ same condition
CA4 p.Asn269= Likely benign ★★ 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/ca4-p-val233 (accessed [today's date]).

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