Is CYC1 p.Pro222Ser (c.664C>T) pathogenic?

CYC1 p.Pro222Ser (c.664C>T) is classified Uncertain significance in CYC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). AlphaMissense: likely pathogenic (0.723); Very rare (popmax 0.00446%, eas).

How common is CYC1 p.Pro222Ser (c.664C>T) in the general population?

CYC1 p.Pro222Ser (c.664C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CYC1 p.Pro222Ser (c.664C>T)?

AlphaMissense predicts likely pathogenic (score 0.723) — an in-silico prediction, not a clinical call.

CYC1 p.Pro222Ser

c.664C>T · VCV4008661

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.723 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.723	likely pathogenic
REVEL	0.681	pathogenic-leaning
SaProt	LLR -11.99	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 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 2,233 bp · p 0.31 · regional, not allelic
Overall
CADD	28.3	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

Grpmax group 0.00446% East Asian · 2/44,864 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000186% 3/1,613,884 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,432
Admixed American	0.00167%	59,992

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: CYC1
Protein: p.Pro222Ser
Coding: c.664C>T
MANE Select: NM_001916
Type: single nucleotide variant
Location: chr8:144096636 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.85 (gnomAD)
Structure: AlphaFold pLDDT 86.37 · 5 PDB
Residue 222: an α-helix

Full CYC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYC1 p.Ala4Val Uncertain significance ★★ ⚠ same type
CYC1 p.Ala5Thr Uncertain significance ★★ ⚠ same type
CYC1 p.Arg285Gln Uncertain significance ★★ ⚠ same type
CYC1 p.Arg287His Uncertain significance ★★ ⚠ same type
CYC1 p.Arg308Gln Uncertain significance ★★ ⚠ same type
CYC1 p.Asn159Ser Uncertain significance ★★ ⚠ same type
CYC1 p.Asp173Asn Uncertain significance ★★ ⚠ same type
CYC1 p.Asp209Asn 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/cyc1-p-pro222ser (accessed [today's date]).

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