Is CA5A p.Pro214Ala (c.640C>G) pathogenic?

CA5A p.Pro214Ala (c.640C>G) is classified Uncertain significance in CA5A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: likely benign (0.0824); Very rare (popmax 0.00547%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CA5A p.Pro214Ala (c.640C>G)?

CA5A p.Pro214Ala (c.640C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CA5A p.Pro214Ala (c.640C>G) in the general population?

CA5A p.Pro214Ala (c.640C>G) is very rare (popmax 0.00547%, nfe) (gnomAD).

What do computational predictors say about CA5A p.Pro214Ala (c.640C>G)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

CA5A p.Pro214Ala

c.640C>G · rs757478646 · VCV2620842

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00547%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -4.94	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 6.1	GERP -4, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.027 · regional, not allelic
Overall
CADD	17.04	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 0.00547% European (non-Finnish) · 63/1,151,178 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00397%

Overall 0.00457% 64/1,401,956 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00547%	18,273
Remaining individualsnot grpmax-eligible	0.00166%	60,206

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.Pro214Ala
Coding: c.640C>G
MANE Select: NM_001739
dbSNP: rs757478646
Type: single nucleotide variant
Location: chr16:87891933 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 214: 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

Similar variants

CA5A p.Ala149Thr Uncertain significance ★★ ⚠ same condition
CA5A p.His143Asp Uncertain significance ★★ ⚠ same condition
CA5A p.Leu259Val Uncertain significance ★★ ⚠ same condition
CA5A p.Phe215Ile Uncertain significance ★★ ⚠ same condition
CA5A p.Pro222Ser Uncertain significance ★★ ⚠ same condition
CA5A p.Pro30Arg Uncertain significance ★★ ⚠ same condition
CA5A p.Thr192Met Uncertain significance ★★ ⚠ same condition
CA5A p.Thr223Asn 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-pro214ala (accessed [today's date]).

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