Is CYC1 p.Val12Ala (c.35T>C) pathogenic?

CYC1 p.Val12Ala (c.35T>C) is classified Uncertain significance in CYC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-09). AlphaMissense: likely benign (0.0702); Ultra-rare (popmax 0.0309%, mid).

How common is CYC1 p.Val12Ala (c.35T>C) in the general population?

CYC1 p.Val12Ala (c.35T>C) is ultra-rare (popmax 0.0309%, mid) (gnomAD).

What do computational predictors say about CYC1 p.Val12Ala (c.35T>C)?

AlphaMissense predicts likely benign (score 0.0702) — an in-silico prediction, not a clinical call.

CYC1 p.Val12Ala

c.35T>C · rs1013518261 · VCV1215351

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0702 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0309%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0702	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -6.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.88	GERP 0.33, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 2,233 bp · p 0.31 · regional, not allelic
Overall
CADD	13.39	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 0.0309% Middle Eastern · 1/3,240 alleles

Filtering AF 0.0158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00983% 119/1,210,282 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0309%	3,240
African / African-American	0.0253%	3,959
Remaining individualsnot grpmax-eligible	0.0159%	6,281
European (non-Finnish)	0.00976%	10,242

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.Val12Ala
Coding: c.35T>C
MANE Select: NM_001916
dbSNP: rs1013518261
Type: single nucleotide variant
Location: chr8:144095134 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.85 (gnomAD)
Structure: AlphaFold pLDDT 86.37 · 5 PDB

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

Similar variants

CYC1 p.Val12Leu 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-val12ala (accessed [today's date]).

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