Is CA5A p.Asp216Ala (c.647A>C) pathogenic?

CA5A p.Asp216Ala (c.647A>C) is classified Uncertain significance in CA5A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-17). AlphaMissense: likely benign (0.1406); Very rare (popmax 0.00791%, amr); Associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.

What condition is associated with CA5A p.Asp216Ala (c.647A>C)?

CA5A p.Asp216Ala (c.647A>C) is associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (ClinVar).

How common is CA5A p.Asp216Ala (c.647A>C) in the general population?

CA5A p.Asp216Ala (c.647A>C) is very rare (popmax 0.00791%, amr) (gnomAD).

What do computational predictors say about CA5A p.Asp216Ala (c.647A>C)?

AlphaMissense predicts likely benign (score 0.1406) — an in-silico prediction, not a clinical call.

CA5A p.Asp216Ala

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.647A>C · rs1344761438 · VCV2161429

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1406 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00791%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Computational evidence

Protein change
AlphaMissense	0.1406	likely benign
REVEL	0.506	indeterminate
SaProt	LLR -10.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.027 · regional, not allelic
Overall
CADD	24.3	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 0.00791% Admixed American · 4/50,578 alleles

Filtering AF 0.00264% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00154%

Overall 0.00045% 7/1,555,458 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00791%	12,644
Remaining individualsnot grpmax-eligible	0.00332%	30,097
European (non-Finnish)	8.68e-05%	1,152,444

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.Asp216Ala
Coding: c.647A>C
MANE Select: NM_001739
dbSNP: rs1344761438
Type: single nucleotide variant
Location: chr16:87891926 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 216: 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.Asp216Asn 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.Gln79Glu 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-asp216ala (accessed [today's date]).

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