Is CA2 p.Ser216= (c.648C>T) pathogenic?

CA2 p.Ser216= (c.648C>T) is classified Benign/Likely benign in CA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-06). Rare (popmax 0.775%, sas); Associated with autosomal recessive osteopetrosis 3.

What condition is associated with CA2 p.Ser216= (c.648C>T)?

CA2 p.Ser216= (c.648C>T) is associated with autosomal recessive osteopetrosis 3 (ClinVar).

How common is CA2 p.Ser216= (c.648C>T) in the general population?

CA2 p.Ser216= (c.648C>T) is rare (popmax 0.775%, sas) (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.Ser216=

c.648C>T · rs376387073 · VCV363836

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.775%, sas)

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 -20	GERP -3.6
Overall
CADD	0.618	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.775% South Asian · 706/91,060 alleles

Filtering AF 0.728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.709%

Overall 0.0463% 747/1,614,078 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.775%	129
Remaining individualsnot grpmax-eligible	0.0464%	2,156
Middle Eastern	0.0165%	6,060
Admixed American	0.00833%	12,002
African / African-American	0.00133%	75,050
European (non-Finnish)	0.000424%	235,995

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.Ser216=
Coding: c.648C>T
MANE Select: NM_000067
dbSNP: rs376387073
Type: single nucleotide variant
Location: chr8:85477260 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 216: the alpha-carbonic anhydrase domain; a β-strand

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 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
CA2 p.Asn67Asp 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-ser216 (accessed [today's date]).

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