Is CA2 p.Ser219= (c.657C>T) pathogenic?

CA2 p.Ser219= (c.657C>T) is classified Conflicting classifications of pathogenicity in CA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-25). Very rare (popmax 0.00534%, afr); Associated with autosomal recessive osteopetrosis 3.

What condition is associated with CA2 p.Ser219= (c.657C>T)?

CA2 p.Ser219= (c.657C>T) is associated with autosomal recessive osteopetrosis 3 (ClinVar).

How common is CA2 p.Ser219= (c.657C>T) in the general population?

CA2 p.Ser219= (c.657C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

How is Osteopetrosis with renal tubular acidosis inherited?

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

CA2 p.Ser219=

c.657C>T · rs148054811 · VCV1495624

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 0.00534%, afr)

Conditions

autosomal recessive osteopetrosis 3

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 -6.7	GERP -3.6
Overall
CADD	8.002	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,908 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00279% 45/1,613,946 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-Americangrpmax	0.00534%	18,727
European (non-Finnish)	0.00305%	32,777
Admixed American	0.00167%	59,990

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: CA2
Protein: p.Ser219=
Coding: c.657C>T
MANE Select: NM_000067
dbSNP: rs148054811
Type: single nucleotide variant
Location: chr8:85477269 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 219: the alpha-carbonic anhydrase domain; an α-helix

Full CA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive osteopetrosis 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Osteopetrosis with renal tubular acidosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CA2 p.Ser219Gly Uncertain significance ★ ⚠ same residue
CA2 c.232+1G>A Pathogenic ★★ same condition
CA2 p.Gln92Pro Likely pathogenic ★★ same condition
CA2 p.Glu204Ter Pathogenic/Likely pathogenic ★★ same condition
CA2 p.Tyr193Ter Likely pathogenic ★★ same condition
CA2 p.Arg181Cys Uncertain significance ★★ ⚠ same condition
CA2 p.Arg181His Uncertain significance ★★ ⚠ same condition
CA2 p.Arg226His Uncertain significance ★★ ⚠ 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/ca2-p-ser219 (accessed [today's date]).

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