Is CA5A p.Pro222Ser (c.664C>T) pathogenic?

CA5A p.Pro222Ser (c.664C>T) is classified Uncertain significance in CA5A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-11). AlphaMissense: ambiguous (0.5615); Ultra-rare (popmax 0.0349%, mid); Associated with Inborn genetic diseases.

What condition is associated with CA5A p.Pro222Ser (c.664C>T)?

CA5A p.Pro222Ser (c.664C>T) is associated with Inborn genetic diseases, hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (ClinVar).

How common is CA5A p.Pro222Ser (c.664C>T) in the general population?

CA5A p.Pro222Ser (c.664C>T) is ultra-rare (popmax 0.0349%, mid) (gnomAD).

What do computational predictors say about CA5A p.Pro222Ser (c.664C>T)?

AlphaMissense predicts ambiguous (score 0.5615) — an in-silico prediction, not a clinical call.

CA5A p.Pro222Ser

c.664C>T · rs749940049 · VCV2057694

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5615 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0349%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5615	ambiguous
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -9.84	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.027 · regional, not allelic
Overall
CADD	23.4	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 0.0349% Middle Eastern · 2/5,728 alleles

Filtering AF 0.00613% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00254%

Overall 0.000636% 9/1,415,390 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0349%	2,864
European (non-Finnish)	0.000604%	165,434

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.Pro222Ser
Coding: c.664C>T
MANE Select: NM_001739
dbSNP: rs749940049
Type: single nucleotide variant
Location: chr16:87891909 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 222: the alpha-carbonic anhydrase domain

Full CA5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Similar variants

CA5A p.Pro222Ala 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.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-pro222ser (accessed [today's date]).

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