Is CIAO2A p.Arg48Trp (c.142C>T) pathogenic?

CIAO2A p.Arg48Trp (c.142C>T) is classified Uncertain significance in CIAO2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: ambiguous (0.5489); Ultra-rare (popmax 0.06%, nfe).

How common is CIAO2A p.Arg48Trp (c.142C>T) in the general population?

CIAO2A p.Arg48Trp (c.142C>T) is ultra-rare (popmax 0.06%, nfe) (gnomAD).

What do computational predictors say about CIAO2A p.Arg48Trp (c.142C>T)?

AlphaMissense predicts ambiguous (score 0.5489) — an in-silico prediction, not a clinical call.

CIAO2A p.Arg48Trp

c.142C>T · rs147426625 · VCV2589521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5489 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5489	ambiguous
REVEL	0.383	indeterminate
SaProt	LLR -15.23	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.97 · regional, not allelic
Overall
CADD	28.7	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 0.06% European (non-Finnish) · 708/1,179,514 alleles

Filtering AF 0.0564% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0549%

Overall 0.0483% 779/1,612,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0657%	1,523
European (non-Finnish)grpmax	0.06%	1,666
Admixed American	0.0303%	3,302
Middle Eastern	0.0165%	6,056
African / African-American	0.00935%	10,695
East Asian	0.00669%	14,947
South Asian	0.0011%	90,538

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg48Trp
Coding: c.142C>T
MANE Select: NM_032231
dbSNP: rs147426625
Type: single nucleotide variant
Location: chr15:64088834 (GRCh38)
Gene constraint: LOEUF 1.054 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 86.90 · 3 PDB

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

Similar variants

CIAO2A p.Arg48Gln Uncertain significance ★ ⚠ same residue
CIAO2A p.Ala140Val Uncertain significance ★ ⚠ same type
CIAO2A p.Arg149Trp Uncertain significance ★ ⚠ same type
CIAO2A p.Arg14Gly 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
CIAO2A p.Glu153Lys 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-arg48trp (accessed [today's date]).

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