Is CD33 p.Thr200Ile (c.599C>T) pathogenic?

CD33 p.Thr200Ile (c.599C>T) is classified Uncertain significance in CD33 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-05). AlphaMissense: likely benign (0.1288); Very rare (popmax 0.0011%, sas).

How common is CD33 p.Thr200Ile (c.599C>T) in the general population?

CD33 p.Thr200Ile (c.599C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CD33 p.Thr200Ile (c.599C>T)?

AlphaMissense predicts likely benign (score 0.1288) — an in-silico prediction, not a clinical call.

CD33 p.Thr200Ile

c.599C>T · rs1274826359 · VCV3140554

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1288 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1288	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.7	GERP -3.7
Regional constraint	o/e 0.91	unconstrained · MANE · 15 kb · p 0.052 · regional, not allelic
Overall
CADD	7.636	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,062 alleles

Overall 6.84e-05% 1/1,461,874 alleles · very rare

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.Thr200Ile
Coding: c.599C>T
MANE Select: NM_001772
dbSNP: rs1274826359
Type: single nucleotide variant
Location: chr19:51225983 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.30 · 11 PDB
Residue 200: a disulfide bond; the ig-like c2-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-thr200ile (accessed [today's date]).

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