Is CIAO2B p.Pro38Leu (c.113C>T) pathogenic?

CIAO2B p.Pro38Leu (c.113C>T) is classified Uncertain significance in CIAO2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-12). AlphaMissense: likely benign (0.1005); Very rare (popmax 0.0039%, nfe).

How common is CIAO2B p.Pro38Leu (c.113C>T) in the general population?

CIAO2B p.Pro38Leu (c.113C>T) is very rare (popmax 0.0039%, nfe) (gnomAD).

What do computational predictors say about CIAO2B p.Pro38Leu (c.113C>T)?

AlphaMissense predicts likely benign (score 0.1005) — an in-silico prediction, not a clinical call.

CIAO2B p.Pro38Leu

c.113C>T · rs781470049 · VCV2622253

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1005 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0039%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1005	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -4.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.71 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,158 bp · p 0.62 · regional, not allelic
Overall
CADD	24.1	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 0.0039% European (non-Finnish) · 46/1,179,630 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00298% 48/1,609,824 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0039%	25,644
Remaining individualsnot grpmax-eligible	0.00321%	31,199

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.Pro38Leu
Coding: c.113C>T
MANE Select: NM_016062
dbSNP: rs781470049
Type: single nucleotide variant
Location: chr16:66934252 (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-pro38leu (accessed [today's date]).

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