Is CA2 p.Ser2Tyr (c.5C>A) pathogenic?

CA2 p.Ser2Tyr (c.5C>A) is classified Uncertain significance in CA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-07). AlphaMissense: ambiguous (0.3643); Very rare (popmax 0.000174%, nfe); Associated with autosomal recessive osteopetrosis 3.

What condition is associated with CA2 p.Ser2Tyr (c.5C>A)?

CA2 p.Ser2Tyr (c.5C>A) is associated with autosomal recessive osteopetrosis 3 (ClinVar).

How common is CA2 p.Ser2Tyr (c.5C>A) in the general population?

CA2 p.Ser2Tyr (c.5C>A) is very rare (popmax 0.000174%, nfe) (gnomAD).

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.Ser2Tyr (c.5C>A)?

AlphaMissense predicts ambiguous (score 0.3643) — an in-silico prediction, not a clinical call.

CA2 p.Ser2Tyr

c.5C>A · VCV3595886

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Conditions

autosomal recessive osteopetrosis 3

Computational evidence

Protein change
AlphaMissense	0.3643	ambiguous
REVEL	0.634	indeterminate
SaProt	LLR -12.12	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 0.75, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,714 bp · p 0.33 · regional, not allelic
Overall
CADD	25.0	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 0.000174% European (non-Finnish) · 2/1,149,858 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000143% 2/1,396,972 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.Ser2Tyr
Coding: c.5C>A
MANE Select: NM_000067
Type: single nucleotide variant
Location: chr8:85464086 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 2: a modified residue (n-acetylserine); a modified residue (phosphoserine)

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.Ser2= Likely benign ★ 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-ser2tyr (accessed [today's date]).

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