Is CA5A p.Gln258His (c.774G>C) pathogenic?

CA5A p.Gln258His (c.774G>C) is classified Uncertain significance in CA5A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). AlphaMissense: likely pathogenic (0.841); Very rare (popmax 0.000657%); Associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.

What condition is associated with CA5A p.Gln258His (c.774G>C)?

CA5A p.Gln258His (c.774G>C) is associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (ClinVar).

How common is CA5A p.Gln258His (c.774G>C) in the general population?

CA5A p.Gln258His (c.774G>C) is very rare (popmax 0.000657%) (gnomAD).

What do computational predictors say about CA5A p.Gln258His (c.774G>C)?

AlphaMissense predicts likely pathogenic (score 0.841) — an in-silico prediction, not a clinical call.

CA5A p.Gln258His

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.774G>C · rs2055718095 · VCV1940348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000657%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Computational evidence

Protein change
AlphaMissense	0.841	likely pathogenic · top 8% in CA5A
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -10.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.44	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.65	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.027 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000657%

Overall 0.000657% 1/152,218 alleles · very rare

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.Gln258His
Coding: c.774G>C
MANE Select: NM_001739
dbSNP: rs2055718095
Type: single nucleotide variant
Location: chr16:87891799 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 258: 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.Ala261Val 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

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-gln258his (accessed [today's date]).

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