Is CD59 p.Leu100Arg (c.299T>G) pathogenic?

CD59 p.Leu100Arg (c.299T>G) is classified Uncertain significance in CD59 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-21). AlphaMissense: likely benign (0.074); Ultra-rare (popmax 0.0187%, sas).

How common is CD59 p.Leu100Arg (c.299T>G) in the general population?

CD59 p.Leu100Arg (c.299T>G) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

What do computational predictors say about CD59 p.Leu100Arg (c.299T>G)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

CD59 p.Leu100Arg

c.299T>G · rs761008545 · VCV1490138

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -8.54	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 -2.3	GERP -1.5
Regional constraint	o/e 0.95	unconstrained · MANE · 12 kb · p 0.52 · regional, not allelic
Overall
CADD	0.033	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 0.0187% South Asian · 17/91,090 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00359% 58/1,614,076 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,358
East Asian	0.00445%	22,448
European (non-Finnish)	0.00322%	31,053
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Leu100Arg
Coding: c.299T>G
MANE Select: NM_000611
dbSNP: rs761008545
Type: single nucleotide variant
Location: chr11:33710214 (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 100: the upar/ly6 domain

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

Similar variants

CD59 p.Leu100Phe Uncertain significance ★ ⚠ same residue
CD59 p.Cys89Tyr Pathogenic ★★ same type
CD59 p.Met1Thr Likely pathogenic ★★ same type
CD59 p.Ala50Val Uncertain significance ★★ ⚠ same type
CD59 p.Arg78Cys Uncertain significance ★★ ⚠ same type
CD59 p.Asn33Thr Uncertain significance ★★ ⚠ same type
CD59 p.Asp92Asn Uncertain significance ★★ ⚠ same type
CD59 p.Thr105Pro 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/cd59-p-leu100arg (accessed [today's date]).

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