Is CA5A p.Ser233Pro (c.697T>C) pathogenic?

CA5A p.Ser233Pro (c.697T>C) is classified Conflicting classifications of pathogenicity in CA5A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2022-09-26). AlphaMissense: likely pathogenic (0.9477); Very rare (popmax 0.00404%, nfe); Associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.

What condition is associated with CA5A p.Ser233Pro (c.697T>C)?

CA5A p.Ser233Pro (c.697T>C) is associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (ClinVar).

How common is CA5A p.Ser233Pro (c.697T>C) in the general population?

CA5A p.Ser233Pro (c.697T>C) is very rare (popmax 0.00404%, nfe) (gnomAD).

What do computational predictors say about CA5A p.Ser233Pro (c.697T>C)?

AlphaMissense predicts likely pathogenic (score 0.9477) — an in-silico prediction, not a clinical call.

CA5A p.Ser233Pro

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.697T>C · rs587777316 · VCV127087

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9477 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00404%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Computational evidence

Protein change
AlphaMissense	0.9477	likely pathogenic · top 1% in CA5A
REVEL	0.957	strongly pathogenic-leaning
SaProt	LLR -14.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.027 · regional, not allelic
Overall
CADD	25.1	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 0.00404% European (non-Finnish) · 47/1,162,196 alleles

Filtering AF 0.00312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00324% 51/1,574,768 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00404%	24,728
Finnishnot grpmax-eligible	0.00321%	31,105
Remaining individualsnot grpmax-eligible	0.00164%	60,868
South Asian	0.00117%	85,822

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.Ser233Pro
Coding: c.697T>C
MANE Select: NM_001739
dbSNP: rs587777316
Type: single nucleotide variant
Location: chr16:87891876 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 233: the alpha-carbonic anhydrase domain; a UniProt-annotated variant site (in ca5ad; decreased carbonate dehydratase activity; decreased protein thermal stability)

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.Ser233= Likely benign ★ 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-ser233pro (accessed [today's date]).

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