Is CD33 p.Ala65Pro (c.193G>C) pathogenic?

CD33 p.Ala65Pro (c.193G>C) is classified Benign in CD33 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2017-12-13). AlphaMissense: ambiguous (0.479); Low-frequency (popmax 3.06%, afr).

How common is CD33 p.Ala65Pro (c.193G>C) in the general population?

CD33 p.Ala65Pro (c.193G>C) is low-frequency (popmax 3.06%, afr) (gnomAD).

What do computational predictors say about CD33 p.Ala65Pro (c.193G>C)?

AlphaMissense predicts ambiguous (score 0.479) — an in-silico prediction, not a clinical call.

CD33 p.Ala65Pro

c.193G>C · rs115684563 · VCV715382

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.479 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.06%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.479	ambiguous
REVEL	0.029	moderately benign-leaning
SaProt	LLR -14.60	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.7	GERP -2.7
Regional constraint	o/e 0.91	unconstrained · MANE · 15 kb · p 0.052 · regional, not allelic
Overall
CADD	9.013	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 3.06% African / African-American · 2,293/75,050 alleles

Filtering AF 2.95% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.91%

Overall 0.208% 3,365/1,614,196 alleles · low-frequency exomes 1,934/1,461,878 · genomes 1,431/152,318 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.06%	33
Admixed American	0.458%	218
Remaining individualsnot grpmax-eligible	0.41%	244
Middle Eastern	0.247%	404
European (non-Finnish)	0.0418%	2,394
South Asian	0.0274%	3,643
East Asian	0.0178%	5,610

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.Ala65Pro
Coding: c.193G>C
MANE Select: NM_001772
dbSNP: rs115684563
Type: single nucleotide variant
Location: chr19:51225373 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.30 · 11 PDB
Residue 65: 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.Arg62Gln Likely 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-ala65pro (accessed [today's date]).

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