Is CA2 p.Leu47= (c.139C>T) pathogenic?

CA2 p.Leu47= (c.139C>T) is classified Likely benign in CA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-28). Ultra-rare (popmax 0.0759%, afr); Associated with autosomal recessive osteopetrosis 3.

What condition is associated with CA2 p.Leu47= (c.139C>T)?

CA2 p.Leu47= (c.139C>T) is associated with autosomal recessive osteopetrosis 3 (ClinVar).

How common is CA2 p.Leu47= (c.139C>T) in the general population?

CA2 p.Leu47= (c.139C>T) is ultra-rare (popmax 0.0759%, 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.Leu47=

c.139C>T · rs145096347 · VCV798273

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0759%, 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 0.25	GERP 0.059, phastCons 0.01
Overall
CADD	8.177	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0759% African / African-American · 57/75,058 alleles

Filtering AF 0.0601% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0544%

Overall 0.00533% 86/1,614,186 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0759%	1,317
Admixed American	0.025%	4,002
Remaining individualsnot grpmax-eligible	0.016%	6,251
European (non-Finnish)	0.000339%	295,000

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.Leu47=
Coding: c.139C>T
MANE Select: NM_000067
dbSNP: rs145096347
Type: single nucleotide variant
Location: chr8:85465376 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 47: 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-leu47 (accessed [today's date]).

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