Is CA5A p.Arg263His (c.788G>A) pathogenic?

CA5A p.Arg263His (c.788G>A) is classified Conflicting classifications of pathogenicity in CA5A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.2281); Rare (popmax 0.998%, sas); Associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.

What condition is associated with CA5A p.Arg263His (c.788G>A)?

CA5A p.Arg263His (c.788G>A) is associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (ClinVar).

How common is CA5A p.Arg263His (c.788G>A) in the general population?

CA5A p.Arg263His (c.788G>A) is rare (popmax 0.998%, sas) (gnomAD).

What do computational predictors say about CA5A p.Arg263His (c.788G>A)?

AlphaMissense predicts likely benign (score 0.2281) — an in-silico prediction, not a clinical call.

CA5A p.Arg263His

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.788G>A · rs201195769 · VCV1652614

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2281 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.998%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Computational evidence

Protein change
AlphaMissense	0.2281	likely benign
REVEL	0.738	pathogenic-leaning
SaProt	LLR -12.08	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.027 · regional, not allelic
Overall
CADD	25.7	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 0.998% South Asian · 908/90,976 alleles

Filtering AF 0.944% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.923%

Overall 0.0613% 989/1,613,076 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.998%	100
Middle Eastern	0.0992%	1,008
Remaining individualsnot grpmax-eligible	0.048%	2,082
Admixed American	0.0184%	5,449
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,857
African / African-American	0.00267%	37,477
European (non-Finnish)	0.00246%	40,667

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.Arg263His
Coding: c.788G>A
MANE Select: NM_001739
dbSNP: rs201195769
Type: single nucleotide variant
Location: chr16:87888259 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 263: 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.Arg263Cys 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
CA5A p.Asp216Ala 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-arg263his (accessed [today's date]).

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