Is CA5A p.Ala261Val (c.782C>T) pathogenic?

CA5A p.Ala261Val (c.782C>T) is classified Uncertain significance in CA5A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-23). AlphaMissense: likely benign (0.0964); Very rare (popmax 0.00167%, amr); Associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.

What condition is associated with CA5A p.Ala261Val (c.782C>T)?

CA5A p.Ala261Val (c.782C>T) is associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (ClinVar).

How common is CA5A p.Ala261Val (c.782C>T) in the general population?

CA5A p.Ala261Val (c.782C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CA5A p.Ala261Val (c.782C>T)?

AlphaMissense predicts likely benign (score 0.0964) — an in-silico prediction, not a clinical call.

CA5A p.Ala261Val

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.782C>T · rs1457571520 · VCV1919855

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Computational evidence

Protein change
AlphaMissense	0.0964	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -9.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.24 · evaluated, not missing
Pangolin	Δ0.24	loss · gain 0.03 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 3	GERP 0.4, phastCons 0.26
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.027 · regional, not allelic
Overall
CADD	13.61	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 0.00167% Admixed American · 1/59,898 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000868% 14/1,612,890 alleles · very rare exomes 13/1,460,764 · genomes 1/152,126 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,898
South Asian	0.0011%	90,946
European (non-Finnish)	0.00102%	98,273

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.Ala261Val
Coding: c.782C>T
MANE Select: NM_001739
dbSNP: rs1457571520
Type: single nucleotide variant
Location: chr16:87888265 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 261: 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.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.Arg26His Uncertain significance ★★ ⚠ same condition
CA5A p.Asp216Ala Uncertain significance ★★ ⚠ same condition
CA5A p.Gln79Glu Uncertain significance ★★ ⚠ same condition
CA5A p.His143Asp 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-ala261val (accessed [today's date]).

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