Is CD33 p.Leu141Ser (c.422T>C) pathogenic?

CD33 p.Leu141Ser (c.422T>C) is classified Uncertain significance in CD33 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely pathogenic (0.6066); Very rare (popmax 0.000254%, nfe).

How common is CD33 p.Leu141Ser (c.422T>C) in the general population?

CD33 p.Leu141Ser (c.422T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CD33 p.Leu141Ser (c.422T>C)?

AlphaMissense predicts likely pathogenic (score 0.6066) — an in-silico prediction, not a clinical call.

CD33 p.Leu141Ser

c.422T>C · rs1450380687 · VCV3140552

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6066 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6066	likely pathogenic · top 9% in CD33
REVEL	0.075	moderately benign-leaning
SaProt	LLR -12.52	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.42	GERP 0.73
Regional constraint	o/e 0.91	unconstrained · MANE · 15 kb · p 0.052 · regional, not allelic
Overall
CADD	19.3	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 0.000254% European (non-Finnish) · 3/1,179,616 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,324 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.Leu141Ser
Coding: c.422T>C
MANE Select: NM_001772
dbSNP: rs1450380687
Type: single nucleotide variant
Location: chr19:51225806 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.30 · 11 PDB
Residue 141: a disulfide bond

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-leu141ser (accessed [today's date]).

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