Is CA2 p.Arg226Cys (c.676C>T) pathogenic?

CA2 p.Arg226Cys (c.676C>T) is classified Uncertain significance in CA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-21). AlphaMissense: ambiguous (0.528); Ultra-rare (popmax 0.0111%, eas).

How common is CA2 p.Arg226Cys (c.676C>T) in the general population?

CA2 p.Arg226Cys (c.676C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about CA2 p.Arg226Cys (c.676C>T)?

AlphaMissense predicts ambiguous (score 0.528) — an in-silico prediction, not a clinical call.

CA2 p.Arg226Cys

c.676C>T · VCV3618428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.528 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.528	ambiguous
REVEL	0.65	pathogenic-leaning
SaProt	LLR -15.31	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.82, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 6,424 bp · p 0.35 · regional, not allelic
Overall
CADD	27.0	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 0.0111% East Asian · 5/44,864 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000821% 12/1,460,822 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,973
Remaining individualsnot grpmax-eligible	0.0016%	62,460
African / African-American	0.00133%	74,964
European (non-Finnish)	0.000424%	235,827

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.Arg226Cys
Coding: c.676C>T
MANE Select: NM_000067
Type: single nucleotide variant
Location: chr8:85480682 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 226: the alpha-carbonic anhydrase domain; a turn

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

Similar variants

CA2 p.Arg226His 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.Arg245Cys 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-arg226cys (accessed [today's date]).

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