Is CA4 p.Arg219Ser (c.655C>A) pathogenic?

CA4 p.Arg219Ser (c.655C>A) is classified Uncertain significance in CA4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2005-01-15). AlphaMissense: likely pathogenic (0.9521); Very rare (popmax 0.000254%, nfe); Associated with retinitis pigmentosa 17.

What condition is associated with CA4 p.Arg219Ser (c.655C>A)?

CA4 p.Arg219Ser (c.655C>A) is associated with retinitis pigmentosa 17 (ClinVar).

How common is CA4 p.Arg219Ser (c.655C>A) in the general population?

CA4 p.Arg219Ser (c.655C>A) is very rare (popmax 0.000254%, 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.Arg219Ser (c.655C>A)?

AlphaMissense predicts likely pathogenic (score 0.9521) — an in-silico prediction, not a clinical call.

CA4 p.Arg219Ser

c.655C>A · rs121434551 · VCV17608

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa 17

Computational evidence

Protein change
AlphaMissense	0.9521	likely pathogenic · top 8% in CA4
REVEL	0.686	pathogenic-leaning
SaProt	LLR -15.63	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 6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 9,386 bp · p 0.89 · regional, not allelic
Overall
CADD	27.8	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,014 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,032 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)grpmax	0.000254%	393,338

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg219Ser
Coding: c.655C>A
MANE Select: NM_000717
dbSNP: rs121434551
Type: single nucleotide variant
Location: chr17:60158357 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 219: a disulfide bond; a UniProt-annotated variant site (in rp17; abolishes carbonate dehydratase activity; impaired slc4a4 cotransporter activity stimulation); 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 17 — 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.Arg219His Likely pathogenic ★ same residue
CA4 p.Arg219Cys Uncertain significance ★ ⚠ same residue
CA4 p.Gly87Glu Uncertain significance ★★ ⚠ same condition
CA4 p.Pro227Leu Uncertain significance ★★ ⚠ same condition
CA4 c.*59G>A Conflicting classifications of pathogenicity ★ same condition
CA4 p.Arg14Trp Conflicting classifications of pathogenicity ★ ⚠ same condition
CA4 p.Arg69His Conflicting classifications of pathogenicity ★ ⚠ same condition
CA4 c.745-9C>G Uncertain significance ★★ same type

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-arg219ser (accessed [today's date]).

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