Is CA5A p.Phe215Ile (c.643T>A) pathogenic?

CA5A p.Phe215Ile (c.643T>A) is classified Uncertain significance in CA5A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-20). AlphaMissense: ambiguous (0.3574); Ultra-rare (popmax 0.0178%, mid); Associated with Inborn genetic diseases.

What condition is associated with CA5A p.Phe215Ile (c.643T>A)?

CA5A p.Phe215Ile (c.643T>A) is associated with Inborn genetic diseases, hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (ClinVar).

How common is CA5A p.Phe215Ile (c.643T>A) in the general population?

CA5A p.Phe215Ile (c.643T>A) is ultra-rare (popmax 0.0178%, mid) (gnomAD).

What do computational predictors say about CA5A p.Phe215Ile (c.643T>A)?

AlphaMissense predicts ambiguous (score 0.3574) — an in-silico prediction, not a clinical call.

CA5A p.Phe215Ile

c.643T>A · rs747371774 · VCV2139845

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3574 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3574	ambiguous
REVEL	0.637	indeterminate
SaProt	LLR -7.74	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.027 · regional, not allelic
Overall
CADD	24.7	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 0.0178% Middle Eastern · 1/5,632 alleles

Filtering AF 0.000367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000266%

Overall 0.000899% 14/1,556,998 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0178%	5,632
Remaining individualsnot grpmax-eligible	0.00664%	15,066
European (non-Finnish)	0.000781%	128,058

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.Phe215Ile
Coding: c.643T>A
MANE Select: NM_001739
dbSNP: rs747371774
Type: single nucleotide variant
Location: chr16:87891930 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 215: 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.Phe215= Benign ★★ 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-phe215ile (accessed [today's date]).

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