Is CA2 p.Asn252Ser (c.755A>G) pathogenic?

CA2 p.Asn252Ser (c.755A>G) is classified Uncertain significance in CA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-30). AlphaMissense: likely benign (0.1006); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CA2 p.Asn252Ser (c.755A>G)?

CA2 p.Asn252Ser (c.755A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CA2 p.Asn252Ser (c.755A>G) in the general population?

CA2 p.Asn252Ser (c.755A>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CA2 p.Asn252Ser (c.755A>G)?

AlphaMissense predicts likely benign (score 0.1006) — an in-silico prediction, not a clinical call.

CA2 p.Asn252Ser

c.755A>G · rs1480143400 · VCV3136127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1006 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1006	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -8.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -3.7
Regional constraint	o/e 1.07	unconstrained · MANE · 6,424 bp · p 0.35 · regional, not allelic
Overall
CADD	0.034	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,880 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,636 alleles · very rare

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.Asn252Ser
Coding: c.755A>G
MANE Select: NM_000067
dbSNP: rs1480143400
Type: single nucleotide variant
Location: chr8:85480761 (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

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

Similar variants

CA2 p.Asn252Asp Benign/Likely benign ★★ ⚠ same residue
CA2 p.Arg181His Uncertain significance ★★ ⚠ same condition
CA2 p.Arg226His Uncertain significance ★★ ⚠ same condition
CA2 p.Asn67Asp Uncertain significance ★★ ⚠ same condition
CA2 p.Asp179Glu Uncertain significance ★★ ⚠ same condition
CA2 p.Gln53Glu Uncertain significance ★★ ⚠ same condition
CA2 p.Glu14Lys Uncertain significance ★★ ⚠ same condition
CA2 p.Glu233Lys 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-asn252ser (accessed [today's date]).

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