Is CIAO2A p.Leu43Ser (c.128T>C) pathogenic?

CIAO2A p.Leu43Ser (c.128T>C) is classified Uncertain significance in CIAO2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-16). AlphaMissense: likely pathogenic (0.6669); Very rare (popmax 0.000764%, nfe).

How common is CIAO2A p.Leu43Ser (c.128T>C) in the general population?

CIAO2A p.Leu43Ser (c.128T>C) is very rare (popmax 0.000764%, nfe) (gnomAD).

What do computational predictors say about CIAO2A p.Leu43Ser (c.128T>C)?

AlphaMissense predicts likely pathogenic (score 0.6669) — an in-silico prediction, not a clinical call.

CIAO2A p.Leu43Ser

c.128T>C · rs1567308602 · VCV2604013

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000764%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6669	likely pathogenic
REVEL	0.642	indeterminate
SaProt	LLR -11.87	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.97 · regional, not allelic
Overall
CADD	24.9	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 0.000764% European (non-Finnish) · 9/1,177,726 alleles

Filtering AF 0.00036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 9/1,452,328 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: CIAO2A
Protein: p.Leu43Ser
Coding: c.128T>C
MANE Select: NM_032231
dbSNP: rs1567308602
Type: single nucleotide variant
Location: chr15:64088848 (GRCh38)
Gene constraint: LOEUF 1.054 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 86.90 · 3 PDB
Residue 43: an α-helix

Full CIAO2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CIAO2A p.Ala140Val Uncertain significance ★ ⚠ same type
CIAO2A p.Arg149Trp Uncertain significance ★ ⚠ same type
CIAO2A p.Arg14Gly Uncertain significance ★ ⚠ same type
CIAO2A p.Arg48Gln Uncertain significance ★ ⚠ same type
CIAO2A p.Arg48Trp Uncertain significance ★ ⚠ same type
CIAO2A p.Cys155Tyr Uncertain significance ★ ⚠ same type
CIAO2A p.Gln105Glu Uncertain significance ★ ⚠ same type
CIAO2A p.Glu150Lys 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/ciao2a-p-leu43ser (accessed [today's date]).

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