Is CA5A p.Ala208Val (c.623C>T) pathogenic?

CA5A p.Ala208Val (c.623C>T) is classified Uncertain significance in CA5A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-20). AlphaMissense: likely benign (0.119); Ultra-rare (popmax 0.0123%, nfe); Associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.

What condition is associated with CA5A p.Ala208Val (c.623C>T)?

CA5A p.Ala208Val (c.623C>T) is associated with hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (ClinVar).

How common is CA5A p.Ala208Val (c.623C>T) in the general population?

CA5A p.Ala208Val (c.623C>T) is ultra-rare (popmax 0.0123%, nfe) (gnomAD).

What do computational predictors say about CA5A p.Ala208Val (c.623C>T)?

AlphaMissense predicts likely benign (score 0.119) — an in-silico prediction, not a clinical call.

CA5A p.Ala208Val

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.623C>T · rs151220382 · VCV1488947

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.119 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Computational evidence

Protein change
AlphaMissense	0.119	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -3.6, phastCons 0.004
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.027 · regional, not allelic
Overall
CADD	16.76	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 0.0123% European (non-Finnish) · 141/1,142,206 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.01%

Overall 0.0102% 156/1,535,426 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0178%	5,628
European (non-Finnish)grpmax	0.0123%	8,101
African / African-American	0.00976%	10,244
Remaining individualsnot grpmax-eligible	0.00505%	19,806

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala208Val
Coding: c.623C>T
MANE Select: NM_001739
dbSNP: rs151220382
Type: single nucleotide variant
Location: chr16:87891950 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 208: 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.Ala208= Likely benign ★ same residue
CA5A p.Ala208Thr 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.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-ala208val (accessed [today's date]).

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