Is CD93 p.Arg496Cys (c.1486C>T) pathogenic?

CD93 p.Arg496Cys (c.1486C>T) is classified Likely benign in CD93 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-11). AlphaMissense: likely benign (0.1637); Ultra-rare (popmax 0.0508%, mid); Associated with CD93-related disorder.

What condition is associated with CD93 p.Arg496Cys (c.1486C>T)?

CD93 p.Arg496Cys (c.1486C>T) is associated with CD93-related disorder (ClinVar).

How common is CD93 p.Arg496Cys (c.1486C>T) in the general population?

CD93 p.Arg496Cys (c.1486C>T) is ultra-rare (popmax 0.0508%, mid) (gnomAD).

What do computational predictors say about CD93 p.Arg496Cys (c.1486C>T)?

AlphaMissense predicts likely benign (score 0.1637) — an in-silico prediction, not a clinical call.

CD93 p.Arg496Cys

c.1486C>T · VCV3350644

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1637 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0508%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CD93-related disorder

Computational evidence

Protein change
AlphaMissense	0.1637	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -9.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.98	GERP -1.6, phastCons 0.005
Regional constraint	o/e 1.09	unconstrained · MANE · 2,239 bp · p 0.011 · regional, not allelic
Overall
CADD	12.81	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 0.0508% Middle Eastern · 3/5,906 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00737%

Overall 0.00804% 128/1,591,070 alleles · ultra-rare exomes 113/1,438,800 · genomes 15/152,270 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.115%	866
Middle Easterngrpmax	0.0508%	1,969
Remaining individualsnot grpmax-eligible	0.0228%	4,382
Admixed American	0.00704%	14,203
European (non-Finnish)	0.0059%	16,947
African / African-American	0.00405%	24,692
South Asian	0.00342%	29,240

Ashkenazi Jewish 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: CD93
Protein: p.Arg496Cys
Coding: c.1486C>T
MANE Select: NM_012072
Type: single nucleotide variant
Location: chr20:23084707 (GRCh38)
Gene constraint: LOEUF 1.237 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.07 · 2 PDB
Residue 496: the 'disordered' region

Full CD93 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CD93-related disorder

Similar variants

CD93 p.Arg496His Likely benign same residue
CD93 p.Arg496= Benign/Likely benign ★★ same residue
CD93 p.Arg634Ter Uncertain significance ★ same condition
CD93 p.Met187Ile Uncertain significance ⚠ same condition
CD93 p.Ser41= Likely benign same condition
CD93 p.Val117Gly Benign ⚠ same condition
CD93 p.Glu484del Likely benign same condition
CD93 p.Gly448= Benign ★★ 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/cd93-p-arg496cys (accessed [today's date]).

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