Is CYC1 p.Pro92Leu (c.275C>T) pathogenic?

CYC1 p.Pro92Leu (c.275C>T) is classified Uncertain significance in CYC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-19). AlphaMissense: likely benign (0.2703); Very rare (popmax 0.00017%, nfe).

How common is CYC1 p.Pro92Leu (c.275C>T) in the general population?

CYC1 p.Pro92Leu (c.275C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CYC1 p.Pro92Leu (c.275C>T)?

AlphaMissense predicts likely benign (score 0.2703) — an in-silico prediction, not a clinical call.

CYC1 p.Pro92Leu

c.275C>T · rs1253333723 · VCV2272410

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2703	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -13.66	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 2,233 bp · p 0.31 · regional, not allelic
Overall
CADD	25.7	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 0.00017% European (non-Finnish) · 2/1,179,434 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,607,202 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.Pro92Leu
Coding: c.275C>T
MANE Select: NM_001916
dbSNP: rs1253333723
Type: single nucleotide variant
Location: chr8:144095978 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.85 (gnomAD)
Structure: AlphaFold pLDDT 86.37 · 5 PDB
Residue 92: an α-helix

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

Similar variants

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CYC1 p.Arg287His Uncertain significance ★★ ⚠ same type
CYC1 p.Arg308Gln Uncertain significance ★★ ⚠ same type
CYC1 p.Asn159Ser Uncertain significance ★★ ⚠ same type
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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-pro92leu (accessed [today's date]).

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