Is CYCS p.Leu99Phe (c.295C>T) pathogenic?

CYCS p.Leu99Phe (c.295C>T) is classified Conflicting classifications of pathogenicity in CYCS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-23). AlphaMissense: likely pathogenic (0.8429); Very rare (popmax 8.48e-05%, nfe); Associated with CYCS-related disorder.

What condition is associated with CYCS p.Leu99Phe (c.295C>T)?

CYCS p.Leu99Phe (c.295C>T) is associated with CYCS-related disorder, thrombocytopenia 4 (ClinVar).

How common is CYCS p.Leu99Phe (c.295C>T) in the general population?

CYCS p.Leu99Phe (c.295C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CYCS p.Leu99Phe (c.295C>T)?

AlphaMissense predicts likely pathogenic (score 0.8429) — an in-silico prediction, not a clinical call.

CYCS p.Leu99Phe

c.295C>T · rs1583394629 · VCV2628903

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8429 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CYCS-related disorder

Computational evidence

Protein change
AlphaMissense	0.8429	likely pathogenic
REVEL	0.78	moderately pathogenic-leaning
SaProt	LLR -11.00	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 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 415 bp · p 0.00062 · regional, not allelic
Overall
CADD	25.8	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 8.48e-05% European (non-Finnish) · 1/1,179,866 alleles

Overall 6.9e-05% 1/1,450,216 alleles · very rare

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: CYCS
Protein: p.Leu99Phe
Coding: c.295C>T
MANE Select: NM_018947
dbSNP: rs1583394629
Type: single nucleotide variant
Location: chr7:25123724 (GRCh38)
Gene constraint: LOEUF 0.335 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 97.95 · 13 PDB
Residue 99: an α-helix

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

Disease context

CYCS-related disorder

Also linked: thrombocytopenia 4

Similar variants

CYCS p.Leu99Val Likely pathogenic same residue
CYCS p.Gly42Ser Likely pathogenic ★★ same condition
CYCS p.Ala52Thr Uncertain significance ★★ ⚠ same condition
CYCS p.Leu33Val Uncertain significance ★★ ⚠ same condition
CYCS c.-6T>G Benign/Likely benign ★★ same condition
CYCS p.Ala97Asp Likely pathogenic ★ same condition
CYCS p.Leu65Val Likely pathogenic ★ same condition
CYCS p.Tyr49His 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/cycs-p-leu99phe (accessed [today's date]).

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