Is CA2 p.Ile145Val (c.433A>G) pathogenic?

CA2 p.Ile145Val (c.433A>G) is classified Conflicting classifications of pathogenicity in CA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-19). AlphaMissense: likely benign (0.0919); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with CA2 p.Ile145Val (c.433A>G)?

CA2 p.Ile145Val (c.433A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CA2 p.Ile145Val (c.433A>G) in the general population?

CA2 p.Ile145Val (c.433A>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CA2 p.Ile145Val (c.433A>G)?

AlphaMissense predicts likely benign (score 0.0919) — an in-silico prediction, not a clinical call.

CA2 p.Ile145Val

c.433A>G · rs768827690 · VCV1399500

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0919 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0919	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -4.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.30	donor loss, 3 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.31	GERP -3.7
Regional constraint	o/e 1.07	unconstrained · MANE · 6,424 bp · p 0.35 · regional, not allelic
Overall
CADD	0.49	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 0.00333% Admixed American · 2/59,970 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000434% 7/1,612,596 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,813
Admixed Americangrpmax	0.00333%	29,985
South Asian	0.0022%	45,535

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile145Val
Coding: c.433A>G
MANE Select: NM_000067
dbSNP: rs768827690
Type: single nucleotide variant
Location: chr8:85474405 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 145: 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.Ile145Thr Uncertain significance ★★ ⚠ 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-ile145val (accessed [today's date]).

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