Is CA4 p.Lys192Arg (c.575A>G) pathogenic?

CA4 p.Lys192Arg (c.575A>G) is classified Conflicting classifications of pathogenicity in CA4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.0899); Ultra-rare (popmax 0.0589%, nfe); Associated with retinitis pigmentosa.

What condition is associated with CA4 p.Lys192Arg (c.575A>G)?

CA4 p.Lys192Arg (c.575A>G) is associated with retinitis pigmentosa (ClinVar).

How common is CA4 p.Lys192Arg (c.575A>G) in the general population?

CA4 p.Lys192Arg (c.575A>G) is ultra-rare (popmax 0.0589%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

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

What do computational predictors say about CA4 p.Lys192Arg (c.575A>G)?

AlphaMissense predicts likely benign (score 0.0899) — an in-silico prediction, not a clinical call.

CA4 p.Lys192Arg

c.575A>G · rs147624521 · VCV324234

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0899 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0589%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.0899	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -6.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.9	GERP -4
Regional constraint	o/e 0.99	unconstrained · MANE · 9,386 bp · p 0.89 · regional, not allelic
Overall
CADD	0.022	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0589% European (non-Finnish) · 695/1,179,722 alleles

Filtering AF 0.0553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0538%

Overall 0.0447% 721/1,613,480 alleles · ultra-rare exomes 691/1,461,602 · genomes 30/151,878 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0589%	1,697
Remaining individualsnot grpmax-eligible	0.0192%	5,205
Finnishnot grpmax-eligible	0.0172%	5,815
African / African-American	0.00267%	37,410
Admixed American	0.00167%	59,990

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.Lys192Arg
Coding: c.575A>G
MANE Select: NM_000717
dbSNP: rs147624521
Type: single nucleotide variant
Location: chr17:60158122 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 192: the alpha-carbonic anhydrase domain

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-lys192arg (accessed [today's date]).

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