Is CA5A p.Leu259= (c.777C>G) pathogenic?

CA5A p.Leu259= (c.777C>G) is classified Likely benign in CA5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). Ultra-rare (popmax 0.0518%, amr); Associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.

What condition is associated with CA5A p.Leu259= (c.777C>G)?

CA5A p.Leu259= (c.777C>G) is associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (ClinVar).

How common is CA5A p.Leu259= (c.777C>G) in the general population?

CA5A p.Leu259= (c.777C>G) is ultra-rare (popmax 0.0518%, amr) (gnomAD).

CA5A p.Leu259=

Q: How is Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.777C>G · rs762128732 · VCV1583105

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0518%, amr)

Conditions

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.24	GERP -3, phastCons 0.98
Overall
CADD	3.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0518% Admixed American · 31/59,868 alleles

Filtering AF 0.0375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0326%

Overall 0.00242% 39/1,612,468 alleles · ultra-rare exomes 37/1,460,316 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0518%	1,931
Remaining individualsnot grpmax-eligible	0.0032%	31,218
African / African-American	0.00134%	74,884
European (non-Finnish)	0.000424%	235,787

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: CA5A
Protein: p.Leu259=
Coding: c.777C>G
MANE Select: NM_001739
dbSNP: rs762128732
Type: single nucleotide variant
Location: chr16:87888270 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 259: the alpha-carbonic anhydrase domain

Full CA5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

CA5A p.Leu259Val Uncertain significance ★★ ⚠ same residue
CA5A p.Leu259Pro Uncertain significance ★ ⚠ same residue
CA5A p.Arg32Ter Pathogenic ★★ same condition
CA5A p.Glu241Lys Pathogenic/Likely pathogenic ★★ same condition
CA5A p.Ala149Thr Uncertain significance ★★ ⚠ same condition
CA5A p.Ala208Val Uncertain significance ★★ ⚠ same condition
CA5A p.Ala261Val Uncertain significance ★★ ⚠ same condition
CA5A p.Arg26His 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/ca5a-p-leu259 (accessed [today's date]).

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