Is CD59 p.Cys89Tyr (c.266G>A) pathogenic?

CD59 p.Cys89Tyr (c.266G>A) is classified Pathogenic in CD59 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-06). AlphaMissense: likely pathogenic (0.9829); Very rare (popmax 8.47e-05%, nfe); Associated with CD59-related disorder.

What condition is associated with CD59 p.Cys89Tyr (c.266G>A)?

CD59 p.Cys89Tyr (c.266G>A) is associated with CD59-related disorder, primary CD59 deficiency (ClinVar).

How common is CD59 p.Cys89Tyr (c.266G>A) in the general population?

CD59 p.Cys89Tyr (c.266G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CD59 p.Cys89Tyr (c.266G>A)?

AlphaMissense predicts likely pathogenic (score 0.9829) — an in-silico prediction, not a clinical call.

CD59 p.Cys89Tyr

c.266G>A · rs397514767 · VCV64690

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CD59-related disorder

Computational evidence

Protein change
AlphaMissense	0.9829	likely pathogenic ✓ concordant with ClinVar · top 4% in CD59
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -14.74	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 6.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 12 kb · p 0.52 · regional, not allelic
Overall
CADD	24.8	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 8.47e-05% European (non-Finnish) · 1/1,180,002 alleles

Overall 0.000342% 5/1,461,822 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,628
European (non-Finnish)grpmax	8.47e-05%	1,180,002

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CD59
Protein: p.Cys89Tyr
Coding: c.266G>A
MANE Select: NM_000611
dbSNP: rs397514767
Type: single nucleotide variant
Location: chr11:33710247 (GRCh38)
Gene constraint: LOEUF 1.277 · pLI 0.57 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.15 · 17 PDB
Residue 89: a disulfide bond; a UniProt-annotated variant site (in hacd59); the upar/ly6 domain; a β-strand

Full CD59 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CD59-related disorder

Also linked: primary CD59 deficiency

Similar variants

CD59 p.Cys89= Likely benign ★ same residue
CD59 p.Met1Thr Likely pathogenic ★★ same condition
CD59 p.Asp49Val Pathogenic ★ same condition
CD59 p.Asn30Ser Uncertain significance ★ ⚠ same condition
CD59 p.Cys28Tyr Conflicting classifications of pathogenicity ★ same condition
CD59 p.Cys64Gly Uncertain significance ★ ⚠ same condition
CD59 p.Tyr29Asp Uncertain significance ★ ⚠ same condition
CD59 p.Asp47_Phe48insTer Likely pathogenic ★ same condition

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/cd59-p-cys89tyr (accessed [today's date]).

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