Is CA2 p.Asn252Asp (c.754A>G) pathogenic?

CA2 p.Asn252Asp (c.754A>G) is classified Benign/Likely benign in CA2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0976); Common (popmax 9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive osteopetrosis 3.

What condition is associated with CA2 p.Asn252Asp (c.754A>G)?

CA2 p.Asn252Asp (c.754A>G) 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.

What do computational predictors say about CA2 p.Asn252Asp (c.754A>G)?

AlphaMissense predicts likely benign (score 0.0976) — an in-silico prediction, not a clinical call.

CA2 p.Asn252Asp

Q: How common is CA2 p.Asn252Asp (c.754A>G) in the general population?

CA2 p.Asn252Asp (c.754A>G) is common (popmax 9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.754A>G · rs2228063 · VCV913

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0976 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive osteopetrosis 3

Computational evidence

Protein change
AlphaMissense	0.0976	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.097	GERP -2.2
Regional constraint	o/e 1.07	unconstrained · MANE · 6,424 bp · p 0.35 · regional, not allelic
Overall
CADD	9.831	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9% African / African-American · 6,751/75,000 alleles

Filtering AF 8.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.75%

Overall 0.471% 7,605/1,613,926 alleles · common exomes 3,642/1,461,630 · genomes 3,963/152,296 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9%	11
Admixed American	0.684%	146
Remaining individualsnot grpmax-eligible	0.531%	188
Middle Eastern	0.215%	466
South Asian	0.0176%	5,693
European (non-Finnish)	0.00703%	14,216

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.Asn252Asp
Coding: c.754A>G
MANE Select: NM_000067
dbSNP: rs2228063
Type: single nucleotide variant
Location: chr8:85480760 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 252: the alpha-carbonic anhydrase domain; a UniProt-annotated variant site (in)

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.Asn252Ser 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-asn252asp (accessed [today's date]).

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