Is CAB39 p.Gln69Pro (c.206A>C) pathogenic?

CAB39 p.Gln69Pro (c.206A>C) is classified Uncertain significance in CAB39 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). AlphaMissense: likely pathogenic (0.9771); Very rare (popmax 8.48e-05%, nfe).

How common is CAB39 p.Gln69Pro (c.206A>C) in the general population?

CAB39 p.Gln69Pro (c.206A>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CAB39 p.Gln69Pro (c.206A>C)?

AlphaMissense predicts likely pathogenic (score 0.9771) — an in-silico prediction, not a clinical call.

CAB39 p.Gln69Pro

c.206A>C · VCV4217575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9771 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9771	likely pathogenic
REVEL	0.675	pathogenic-leaning
SaProt	LLR -12.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 59 kb · p 6e-11 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,072 alleles

Overall 6.85e-05% 1/1,460,728 alleles · very rare

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: CAB39
Protein: p.Gln69Pro
Coding: c.206A>C
MANE Select: NM_016289
Type: single nucleotide variant
Location: chr2:230790963 (GRCh38)
Gene constraint: LOEUF 0.693 · pLI 0.67 (gnomAD)
Structure: AlphaFold pLDDT 94.77 · 10 PDB
Residue 69: an α-helix

Full CAB39 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAB39 p.Asp239Glu Uncertain significance ★ ⚠ same type
CAB39 p.Ile110Thr Uncertain significance ★ ⚠ same type
CAB39 p.Ile303Met Uncertain significance ★ ⚠ same type
CAB39 p.Leu296Phe Uncertain significance ★ ⚠ same type
CAB39 p.Lys10Arg Uncertain significance ★ ⚠ same type
CAB39 p.Met50Val Uncertain significance ★ ⚠ same type
CAB39 p.Phe185Tyr Uncertain significance ★ ⚠ same type
CAB39 p.Phe210Leu 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/cab39-p-gln69pro (accessed [today's date]).

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