Is CA2 p.Arg245Cys (c.733C>T) pathogenic?

CA2 p.Arg245Cys (c.733C>T) is classified Uncertain significance in CA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-05-30). AlphaMissense: likely pathogenic (0.9237); Very rare (popmax 0.005%, amr).

How common is CA2 p.Arg245Cys (c.733C>T) in the general population?

CA2 p.Arg245Cys (c.733C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CA2 p.Arg245Cys (c.733C>T)?

AlphaMissense predicts likely pathogenic (score 0.9237) — an in-silico prediction, not a clinical call.

CA2 p.Arg245Cys

c.733C>T · rs745556921 · VCV1309474

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9237 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9237	likely pathogenic
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -11.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.94, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 6,424 bp · p 0.35 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.005% Admixed American · 3/59,958 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00155% 25/1,613,678 alleles · very rare exomes 24/1,461,526 · genomes 1/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,986
East Asian	0.00223%	44,886
European (non-Finnish)	0.0017%	58,988
South Asian	0.0011%	91,082

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.Arg245Cys
Coding: c.733C>T
MANE Select: NM_000067
dbSNP: rs745556921
Type: single nucleotide variant
Location: chr8:85480739 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 245: the alpha-carbonic anhydrase domain; an α-helix

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

Similar variants

CA2 p.Arg245His Uncertain significance ★ ⚠ same residue
CA2 c.232+1G>A Pathogenic ★★ same type
CA2 p.Gln92Pro Likely pathogenic ★★ same type
CA2 p.Glu204Ter Pathogenic/Likely pathogenic ★★ same type
CA2 p.Tyr193Ter Likely pathogenic ★★ same type
CA2 p.Arg181Cys Uncertain significance ★★ ⚠ same type
CA2 p.Arg181His Uncertain significance ★★ ⚠ same type
CA2 p.Arg226His Uncertain significance ★★ ⚠ same type

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-arg245cys (accessed [today's date]).

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