Is CA4 p.Ala251= (c.753A>T) pathogenic?

CA4 p.Ala251= (c.753A>T) is classified Conflicting classifications of pathogenicity in CA4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-08-04). Ultra-rare (popmax 0.0148%, nfe); Associated with retinitis pigmentosa.

What condition is associated with CA4 p.Ala251= (c.753A>T)?

CA4 p.Ala251= (c.753A>T) is associated with retinitis pigmentosa (ClinVar).

How common is CA4 p.Ala251= (c.753A>T) in the general population?

CA4 p.Ala251= (c.753A>T) is ultra-rare (popmax 0.0148%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

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

CA4 p.Ala251=

c.753A>T · rs140515828 · VCV794109

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, nfe)

Conditions

retinitis pigmentosa

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.2	GERP -2.3
Overall
CADD	0.533	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0148% European (non-Finnish) · 174/1,174,040 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0123%

Overall 0.0116% 186/1,601,484 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0148%	6,747
Remaining individualsnot grpmax-eligible	0.00967%	10,337
African / African-American	0.00671%	14,902
Admixed American	0.00171%	58,458

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.Ala251=
Coding: c.753A>T
MANE Select: NM_000717
dbSNP: rs140515828
Type: single nucleotide variant
Location: chr17:60159238 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 251: the alpha-carbonic anhydrase domain; an α-helix

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.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
CA4 p.Gln79Lys 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-ala251 (accessed [today's date]).

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