Is CD33 p.Arg69Gly (c.205A>G) pathogenic?

CD33 p.Arg69Gly (c.205A>G) is classified Benign in CD33 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-08-22). AlphaMissense: likely benign (0.1202); Common (popmax 50.2%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CD33 p.Arg69Gly (c.205A>G)?

AlphaMissense predicts likely benign (score 0.1202) — an in-silico prediction, not a clinical call.

CD33 p.Arg69Gly

Q: How common is CD33 p.Arg69Gly (c.205A>G) in the general population?

CD33 p.Arg69Gly (c.205A>G) is common (popmax 50.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.205A>G · rs2455069 · VCV1225488

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1202 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 50.2%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1202	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -11.09	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.5
Regional constraint	o/e 0.91	unconstrained · MANE · 15 kb · p 0.052 · regional, not allelic
Overall
CADD	0.043	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 50.2% African / African-American · 37,612/74,936 alleles

Filtering AF 49.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 49.6%

Overall 40% 644,836/1,613,862 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	50.4%	2
African / African-Americangrpmax	50.2%	2
European (non-Finnish)	42.6%	2
Middle Eastern	40.5%	2
Ashkenazi Jewishnot grpmax-eligible	39.3%	3
Remaining individualsnot grpmax-eligible	38.7%	3
Finnishnot grpmax-eligible	38.3%	3
South Asian	25.5%	4
Admixed American	24.9%	4
East Asian	6.33%	16

Amish 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: CD33
Protein: p.Arg69Gly
Coding: c.205A>G
MANE Select: NM_001772
dbSNP: rs2455069
Type: single nucleotide variant
Location: chr19:51225385 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.30 · 11 PDB
Residue 69: a disulfide bond; a UniProt-annotated variant site (in); a turn; the ig-like v-type domain

Full CD33 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD33 p.Asp51Asn Uncertain significance ★★ ⚠ same type
CD33 c.924+295A>G Benign ★★ same type
CD33 c.924+296C>T Benign ★★ same type
CD33 c.924+2T>C Benign ★★ same type
CD33 c.924+469G>C Benign ★★ same type
CD33 c.*201G>C Benign ★★ same type
CD33 p.Ala14Val Benign ★★ ⚠ same type
CD33 p.Ala65Pro 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/cd33-p-arg69gly (accessed [today's date]).

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