Is CA5A p.Leu270Pro (c.809T>C) pathogenic?

CA5A p.Leu270Pro (c.809T>C) is classified Uncertain significance in CA5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: likely benign (0.0563); Ultra-rare (popmax 0.015%, amr); Associated with Inborn genetic diseases.

What condition is associated with CA5A p.Leu270Pro (c.809T>C)?

CA5A p.Leu270Pro (c.809T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CA5A p.Leu270Pro (c.809T>C) in the general population?

CA5A p.Leu270Pro (c.809T>C) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about CA5A p.Leu270Pro (c.809T>C)?

AlphaMissense predicts likely benign (score 0.0563) — an in-silico prediction, not a clinical call.

CA5A p.Leu270Pro

c.809T>C · VCV4601914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0563 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0563	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -3.99	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 -3.9	GERP -3.7
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.027 · regional, not allelic
Overall
CADD	0.009	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 0.015% Admixed American · 9/59,988 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.000682% 11/1,613,802 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,665
Remaining individualsnot grpmax-eligible	0.0016%	62,464
African / African-American	0.00134%	74,906

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.Leu270Pro
Coding: c.809T>C
MANE Select: NM_001739
Type: single nucleotide variant
Location: chr16:87888238 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 270: 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-leu270pro (accessed [today's date]).

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