Is CA5A p.Thr229Ile (c.686C>T) pathogenic?

CA5A p.Thr229Ile (c.686C>T) is classified Uncertain significance in CA5A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-13). AlphaMissense: ambiguous (0.5519); Absent from gnomAD v4.1.

How common is CA5A p.Thr229Ile (c.686C>T) in the general population?

CA5A p.Thr229Ile (c.686C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CA5A p.Thr229Ile (c.686C>T)?

AlphaMissense predicts ambiguous (score 0.5519) — an in-silico prediction, not a clinical call.

CA5A p.Thr229Ile

c.686C>T · VCV3370909

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5519 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,574,976)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5519	ambiguous
REVEL	0.674	pathogenic-leaning
SaProt	LLR -14.67	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.027 · regional, not allelic
Overall
CADD	25.4	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

No allele count reported in gnomAD v4.1 (AN 1,574,976). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CA5A
Protein: p.Thr229Ile
Coding: c.686C>T
MANE Select: NM_001739
Type: single nucleotide variant
Location: chr16:87891887 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 229: the alpha-carbonic anhydrase domain

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

Similar variants

CA5A p.Thr229= Likely benign ★ same residue
CA5A p.Arg32Ter Pathogenic ★★ same type
CA5A p.Glu241Lys Pathogenic/Likely pathogenic ★★ same type
CA5A p.Ala149Thr Uncertain significance ★★ ⚠ same type
CA5A p.Ala208Val Uncertain significance ★★ ⚠ same type
CA5A p.Ala261Val Uncertain significance ★★ ⚠ same type
CA5A p.Arg26His Uncertain significance ★★ ⚠ same type
CA5A p.Asp216Ala Uncertain significance ★★ ⚠ same type

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-thr229ile (accessed [today's date]).

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