Is CYCS p.Ala97Asp (c.290C>A) pathogenic?

CYCS p.Ala97Asp (c.290C>A) is classified Likely pathogenic in CYCS (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.5216); Very rare (popmax 6.89e-05%); Associated with thrombocytopenia 4.

What condition is associated with CYCS p.Ala97Asp (c.290C>A)?

CYCS p.Ala97Asp (c.290C>A) is associated with thrombocytopenia 4 (ClinVar).

How common is CYCS p.Ala97Asp (c.290C>A) in the general population?

CYCS p.Ala97Asp (c.290C>A) is very rare (popmax 6.89e-05%) (gnomAD).

What do computational predictors say about CYCS p.Ala97Asp (c.290C>A)?

AlphaMissense predicts ambiguous (score 0.5216) — an in-silico prediction, not a clinical call.

CYCS p.Ala97Asp

c.290C>A · rs2535205469 · VCV1703823

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5216 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.89e-05%)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

thrombocytopenia 4

Computational evidence

Protein change
AlphaMissense	0.5216	ambiguous
REVEL	0.768	pathogenic-leaning
SaProt	LLR -12.51	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.38 · evaluated, not missing
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	25.9	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 6.89e-05%

Overall 6.89e-05% 1/1,451,274 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.Ala97Asp
Coding: c.290C>A
MANE Select: NM_018947
dbSNP: rs2535205469
Type: single nucleotide variant
Location: chr7:25123729 (GRCh38)
Gene constraint: LOEUF 0.335 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 97.95 · 13 PDB
Residue 97: an α-helix

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.Ala97Thr Uncertain significance ★ ⚠ 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.Tyr49His Pathogenic ★ same condition
CYCS c.170-3T>C Conflicting classifications of pathogenicity ★ same condition
CYCS p.His27Tyr 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-ala97asp (accessed [today's date]).

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