Is CD22 p.Cys219Phe (c.656G>T) pathogenic?

CD22 p.Cys219Phe (c.656G>T) is classified Uncertain significance in CD22 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: likely pathogenic (0.9352); Very rare (popmax 0.000169%, nfe).

How common is CD22 p.Cys219Phe (c.656G>T) in the general population?

CD22 p.Cys219Phe (c.656G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CD22 p.Cys219Phe (c.656G>T)?

AlphaMissense predicts likely pathogenic (score 0.9352) — an in-silico prediction, not a clinical call.

CD22 p.Cys219Phe

c.656G>T · rs2513634929 · VCV3140452

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9352	likely pathogenic · top 3% in CD22
REVEL	0.857	moderately pathogenic-leaning
SaProt	LLR -15.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000169% European (non-Finnish) · 2/1,180,008 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,188 alleles · very rare exomes 2/1,461,868 · genomes 0/152,320 · joint denominator

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: CD22
Protein: p.Cys219Phe
Coding: c.656G>T
MANE Select: NM_001771
dbSNP: rs2513634929
Type: single nucleotide variant
Location: chr19:35336279 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.33 · 7 PDB
Residue 219: a disulfide bond; the ig-like c2-type 1 domain; a β-strand

Full CD22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD22 p.Ala391Thr Benign ★★ same type
CD22 p.Cys265= Benign ★★ same type
CD22 p.Gly551Arg Benign ★★ same type
CD22 p.Gly727Ser Likely benign ★★ same type
CD22 p.Pro681= Benign ★★ same type
CD22 p.Ala17Val Uncertain significance ★ ⚠ same type
CD22 p.Ala498Ser Uncertain significance ★ ⚠ same type
CD22 p.Ala656Thr Uncertain significance ★ ⚠ 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/cd22-p-cys219phe (accessed [today's date]).

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