Is CA2 p.Asn67Asp (c.199A>G) pathogenic?

CA2 p.Asn67Asp (c.199A>G) is classified Uncertain significance in CA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-28). AlphaMissense: ambiguous (0.3955); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CA2 p.Asn67Asp (c.199A>G)?

CA2 p.Asn67Asp (c.199A>G) is associated with Inborn genetic diseases, autosomal recessive osteopetrosis 3 (ClinVar).

How common is CA2 p.Asn67Asp (c.199A>G) in the general population?

CA2 p.Asn67Asp (c.199A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CA2 p.Asn67Asp (c.199A>G)?

AlphaMissense predicts ambiguous (score 0.3955) — an in-silico prediction, not a clinical call.

CA2 p.Asn67Asp

c.199A>G · VCV3595895

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3955 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3955	ambiguous
REVEL	0.122	moderately benign-leaning
SaProt	LLR -7.77	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.58, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,714 bp · p 0.33 · regional, not allelic
Overall
CADD	24.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CA2
Protein: p.Asn67Asp
Coding: c.199A>G
MANE Select: NM_000067
Type: single nucleotide variant
Location: chr8:85465436 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 67: a functional site (fine-tunes the proton-transfer properties of h-64; involved in the binding of some activators, including histamine and l-histidine); the alpha-carbonic anhydrase domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive osteopetrosis 3

Similar variants

CA2 p.Asn67Lys 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-asn67asp (accessed [today's date]).

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