Is CIAO2B p.Pro123Leu (c.368C>T) pathogenic?

CIAO2B p.Pro123Leu (c.368C>T) is classified Uncertain significance in CIAO2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: ambiguous (0.5109); Ultra-rare (popmax 0.0177%, sas).

How common is CIAO2B p.Pro123Leu (c.368C>T) in the general population?

CIAO2B p.Pro123Leu (c.368C>T) is ultra-rare (popmax 0.0177%, sas) (gnomAD).

What do computational predictors say about CIAO2B p.Pro123Leu (c.368C>T)?

AlphaMissense predicts ambiguous (score 0.5109) — an in-silico prediction, not a clinical call.

CIAO2B p.Pro123Leu

c.368C>T · VCV4228824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5109 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0177%, sas)

Computational evidence

Protein change
AlphaMissense	0.5109	ambiguous
REVEL	0.418	indeterminate
SaProt	LLR -12.46	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP -0.56, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,158 bp · p 0.62 · regional, not allelic
Overall
CADD	33.0	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 0.0177% South Asian · 16/90,564 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00903%

Overall 0.0018% 29/1,611,786 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0177%	5,660
African / African-American	0.00401%	24,920
European (non-Finnish)	0.000848%	117,905

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: CIAO2B
Protein: p.Pro123Leu
Coding: c.368C>T
MANE Select: NM_016062
Type: single nucleotide variant
Location: chr16:66932806 (GRCh38)
Gene constraint: LOEUF 1.681 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.56

Full CIAO2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CIAO2B p.Arg114His Uncertain significance ★ ⚠ same type
CIAO2B p.Arg162His Uncertain significance ★ ⚠ same type
CIAO2B p.Asn16Asp Uncertain significance ★ ⚠ same type
CIAO2B p.Asn16Lys Uncertain significance ★ ⚠ same type
CIAO2B p.Asp77Asn Uncertain significance ★ ⚠ same type
CIAO2B p.Glu129Gln Uncertain significance ★ ⚠ same type
CIAO2B p.Glu33Gly Uncertain significance ★ ⚠ same type
CIAO2B p.Glu64Lys 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/ciao2b-p-pro123leu (accessed [today's date]).

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