Is CD33 p.Phe243Leu (c.727T>C) pathogenic?

CD33 p.Phe243Leu (c.727T>C) is classified Benign in CD33 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-06-10). AlphaMissense: likely benign (0.3255); Common (popmax 10.9%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CD33 p.Phe243Leu (c.727T>C)?

AlphaMissense predicts likely benign (score 0.3255) — an in-silico prediction, not a clinical call.

CD33 p.Phe243Leu

Q: How common is CD33 p.Phe243Leu (c.727T>C) in the general population?

CD33 p.Phe243Leu (c.727T>C) is common (popmax 10.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.727T>C · rs11882250 · VCV1235113

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3255 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3255	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -4.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -3.3
Regional constraint	o/e 0.91	unconstrained · MANE · 15 kb · p 0.052 · regional, not allelic
Overall
CADD	4.173	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 10.9% African / African-American · 8,147/74,978 alleles

Filtering AF 10.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.6%

Overall 0.582% 9,377/1,611,474 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.9%	9
Admixed American	0.825%	121
Remaining individualsnot grpmax-eligible	0.721%	139
Middle Eastern	0.396%	253
South Asian	0.0264%	3,793
European (non-Finnish)	0.0201%	4,978

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.Phe243Leu
Coding: c.727T>C
MANE Select: NM_001772
dbSNP: rs11882250
Type: single nucleotide variant
Location: chr19:51226338 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.30 · 11 PDB
Residue 243: a UniProt-annotated variant site (in)

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-phe243leu (accessed [today's date]).

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