Is CYC1 p.Ala243Pro (c.727G>C) pathogenic?

CYC1 p.Ala243Pro (c.727G>C) is classified Uncertain significance in CYC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely pathogenic (0.8966); Very rare (popmax 0.000424%, nfe).

How common is CYC1 p.Ala243Pro (c.727G>C) in the general population?

CYC1 p.Ala243Pro (c.727G>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CYC1 p.Ala243Pro (c.727G>C)?

AlphaMissense predicts likely pathogenic (score 0.8966) — an in-silico prediction, not a clinical call.

CYC1 p.Ala243Pro

c.727G>C · VCV4236608

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8966	likely pathogenic
REVEL	0.238	benign-leaning
SaProt	LLR -14.49	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP -0.74, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 2,233 bp · p 0.31 · regional, not allelic
Overall
CADD	23.1	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 0.000424% European (non-Finnish) · 5/1,178,676 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,408 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: CYC1
Protein: p.Ala243Pro
Coding: c.727G>C
MANE Select: NM_001916
Type: single nucleotide variant
Location: chr8:144096699 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.85 (gnomAD)
Structure: AlphaFold pLDDT 86.37 · 5 PDB
Residue 243: a β-strand

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

Similar variants

CYC1 p.Ala243Thr Uncertain significance ★ ⚠ same residue
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

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-ala243pro (accessed [today's date]).

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