Is CYCS p.Leu33Val (c.97C>G) pathogenic?

CYCS p.Leu33Val (c.97C>G) is classified Uncertain significance in CYCS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-18). AlphaMissense: likely pathogenic (0.7704); Absent from gnomAD v4.1; Associated with thrombocytopenia 4.

What condition is associated with CYCS p.Leu33Val (c.97C>G)?

CYCS p.Leu33Val (c.97C>G) is associated with thrombocytopenia 4 (ClinVar).

How common is CYCS p.Leu33Val (c.97C>G) in the general population?

CYCS p.Leu33Val (c.97C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYCS p.Leu33Val (c.97C>G)?

AlphaMissense predicts likely pathogenic (score 0.7704) — an in-silico prediction, not a clinical call.

CYCS p.Leu33Val

c.97C>G · rs2128577598 · VCV1676752

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7704 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombocytopenia 4

Computational evidence

Protein change
AlphaMissense	0.7704	likely pathogenic
REVEL	0.781	moderately pathogenic-leaning
SaProt	LLR -12.66	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 0.93, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 415 bp · p 0.00062 · regional, not allelic
Overall
CADD	26.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CYCS
Protein: p.Leu33Val
Coding: c.97C>G
MANE Select: NM_018947
dbSNP: rs2128577598
Type: single nucleotide variant
Location: chr7:25124023 (GRCh38)
Gene constraint: LOEUF 0.335 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 97.95 · 13 PDB

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

Disease context

thrombocytopenia 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CYCS p.Gly42Ser Likely pathogenic ★★ same condition
CYCS p.Ala52Thr Uncertain significance ★★ ⚠ same condition
CYCS c.-6T>G Benign/Likely benign ★★ same condition
CYCS p.Ala97Asp Likely pathogenic ★ ⚠ same condition
CYCS p.Tyr49His Pathogenic ★ same condition
CYCS c.170-3T>C Conflicting classifications of pathogenicity ★ same condition
CYCS p.His27Tyr Conflicting classifications of pathogenicity ★ same condition
CYCS p.Leu99Phe Conflicting classifications of pathogenicity ★ ⚠ 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/cycs-p-leu33val (accessed [today's date]).

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