Is CA2 p.Leu90Ser (c.269T>C) pathogenic?

CA2 p.Leu90Ser (c.269T>C) is classified Uncertain significance in CA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.9798); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CA2 p.Leu90Ser (c.269T>C)?

CA2 p.Leu90Ser (c.269T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CA2 p.Leu90Ser (c.269T>C) in the general population?

CA2 p.Leu90Ser (c.269T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CA2 p.Leu90Ser (c.269T>C)?

AlphaMissense predicts likely pathogenic (score 0.9798) — an in-silico prediction, not a clinical call.

CA2 p.Leu90Ser

c.269T>C · VCV4217523

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9798 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9798	likely pathogenic · top 4% in CA2
REVEL	0.887	moderately pathogenic-leaning
SaProt	LLR -9.96	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,714 bp · p 0.33 · regional, not allelic
Overall
CADD	25.3	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.Leu90Ser
Coding: c.269T>C
MANE Select: NM_000067
Type: single nucleotide variant
Location: chr8:85473729 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 90: 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

Similar variants

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
CA2 p.Ile145Thr 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-leu90ser (accessed [today's date]).

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