Is CA2 p.Leu188= (c.562T>C) pathogenic?

CA2 p.Leu188= (c.562T>C) is classified Benign in CA2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 71.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive osteopetrosis 3.

What condition is associated with CA2 p.Leu188= (c.562T>C)?

CA2 p.Leu188= (c.562T>C) is associated with autosomal recessive osteopetrosis 3 (ClinVar).

How is Osteopetrosis with renal tubular acidosis inherited?

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

CA2 p.Leu188=

Q: How common is CA2 p.Leu188= (c.562T>C) in the general population?

CA2 p.Leu188= (c.562T>C) is common (popmax 71.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.562T>C · rs703 · VCV254787

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 71.1%, afr) — too common for a highly-penetrant pathogenic allele

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 -1.7	GERP -3.7
Overall
CADD	0.747	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 71.1% African / African-American · 53,209/74,878 alleles

Filtering AF 70.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 70.3%

Overall 59.9% 967,194/1,613,494 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	71.1%	1
Finnishnot grpmax-eligible	68.5%	1
Middle Eastern	62.8%	2
European (non-Finnish)	61%	2
Remaining individualsnot grpmax-eligible	59.8%	2
Ashkenazi Jewishnot grpmax-eligible	56.2%	2
Admixed American	53.8%	2
Amishnot grpmax-eligible	49.7%	2
South Asian	44.8%	2
East Asian	44%	2

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.Leu188=
Coding: c.562T>C
MANE Select: NM_000067
dbSNP: rs703
Type: single nucleotide variant
Location: chr8:85477174 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 188: the alpha-carbonic anhydrase domain

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-leu188 (accessed [today's date]).

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