Is CYCS p.Ala52Thr (c.154G>A) pathogenic?

CYCS p.Ala52Thr (c.154G>A) is classified Uncertain significance in CYCS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-12). AlphaMissense: likely benign (0.3133); Very rare (popmax 8.47e-05%, nfe); Associated with thrombocytopenia 4.

What condition is associated with CYCS p.Ala52Thr (c.154G>A)?

CYCS p.Ala52Thr (c.154G>A) is associated with thrombocytopenia 4 (ClinVar).

How common is CYCS p.Ala52Thr (c.154G>A) in the general population?

CYCS p.Ala52Thr (c.154G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CYCS p.Ala52Thr (c.154G>A)?

AlphaMissense predicts likely benign (score 0.3133) — an in-silico prediction, not a clinical call.

CYCS p.Ala52Thr

c.154G>A · rs573366932 · VCV810076

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3133 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

thrombocytopenia 4

Computational evidence

Protein change
AlphaMissense	0.3133	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -9.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 415 bp · p 0.00062 · regional, not allelic
Overall
CADD	23.8	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 8.47e-05% European (non-Finnish) · 1/1,180,040 alleles

Overall 0.000657% 1/152,262 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.Ala52Thr
Coding: c.154G>A
MANE Select: NM_018947
dbSNP: rs573366932
Type: single nucleotide variant
Location: chr7:25123966 (GRCh38)
Gene constraint: LOEUF 0.335 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 97.95 · 13 PDB
Residue 52: 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.Ala52Val Uncertain significance ★ ⚠ same residue
CYCS p.Gly42Ser Likely pathogenic ★★ 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.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-ala52thr (accessed [today's date]).

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