Is CD33 p.Gly304Arg (c.910G>A) pathogenic?

CD33 p.Gly304Arg (c.910G>A) is classified Benign in CD33 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-03-13). AlphaMissense: likely benign (0.1138); Common (popmax 21.5%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CD33 p.Gly304Arg (c.910G>A)?

AlphaMissense predicts likely benign (score 0.1138) — an in-silico prediction, not a clinical call.

CD33 p.Gly304Arg

Q: How common is CD33 p.Gly304Arg (c.910G>A) in the general population?

CD33 p.Gly304Arg (c.910G>A) is common (popmax 21.5%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.910G>A · rs35112940 · VCV1237638

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1138 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 21.5%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1138	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	donor gain · deltas
Pangolin	Δ0.39	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -7.4	GERP -3
Regional constraint	o/e 0.91	unconstrained · MANE · 15 kb · p 0.052 · regional, not allelic
Overall
CADD	5.618	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 21.5% European (non-Finnish) · 253,899/1,179,352 alleles

Filtering AF 21.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.4%

Overall 18.5% 298,531/1,612,898 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	26.2%	4
European (non-Finnish)grpmax	21.5%	5
Remaining individualsnot grpmax-eligible	16%	6
Amishnot grpmax-eligible	14.3%	7
Ashkenazi Jewishnot grpmax-eligible	14%	7
Middle Eastern	10.7%	9
Admixed American	8.76%	11
South Asian	4.88%	20
African / African-American	4.38%	23
East Asian	0.029%	3,451

Finnish 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.Gly304Arg
Coding: c.910G>A
MANE Select: NM_001772
dbSNP: rs35112940
Type: single nucleotide variant
Location: chr19:51235662 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.30 · 11 PDB
Residue 304: a UniProt-annotated variant site (in); the 'disordered' region

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-gly304arg (accessed [today's date]).

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