Is CA2 p.Val217Ile (c.649G>A) pathogenic?

CA2 p.Val217Ile (c.649G>A) is classified Uncertain significance in CA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-01-11). AlphaMissense: likely benign (0.0884); Ultra-rare (popmax 0.0165%, mid); Associated with autosomal recessive osteopetrosis 3.

What condition is associated with CA2 p.Val217Ile (c.649G>A)?

CA2 p.Val217Ile (c.649G>A) is associated with autosomal recessive osteopetrosis 3 (ClinVar).

How common is CA2 p.Val217Ile (c.649G>A) in the general population?

CA2 p.Val217Ile (c.649G>A) is ultra-rare (popmax 0.0165%, mid) (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.Val217Ile (c.649G>A)?

AlphaMissense predicts likely benign (score 0.0884) — an in-silico prediction, not a clinical call.

CA2 p.Val217Ile

c.649G>A · rs539558180 · VCV850547

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0884 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive osteopetrosis 3

Computational evidence

Protein change
AlphaMissense	0.0884	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -1.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.082	GERP 0.01
Regional constraint	o/e 1.07	unconstrained · MANE · 6,424 bp · p 0.35 · regional, not allelic
Overall
CADD	16.59	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.0044% 71/1,614,072 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0064%	15,627
European (non-Finnish)	0.005%	19,999
South Asian	0.0022%	45,535
African / African-American	0.00133%	75,030

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.Val217Ile
Coding: c.649G>A
MANE Select: NM_000067
dbSNP: rs539558180
Type: single nucleotide variant
Location: chr8:85477261 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 217: the alpha-carbonic anhydrase domain; a β-strand

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.Val217= Conflicting classifications of pathogenicity ★ 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-val217ile (accessed [today's date]).

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