Is CYLC2 p.Lys328Arg (c.983A>G) pathogenic?

CYLC2 p.Lys328Arg (c.983A>G) is classified Uncertain significance in CYLC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-21). AlphaMissense: likely benign (0.1809); Very rare (popmax 8.48e-05%, nfe).

How common is CYLC2 p.Lys328Arg (c.983A>G) in the general population?

CYLC2 p.Lys328Arg (c.983A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CYLC2 p.Lys328Arg (c.983A>G)?

AlphaMissense predicts likely benign (score 0.1809) — an in-silico prediction, not a clinical call.

CYLC2 p.Lys328Arg

c.983A>G · rs1354650905 · VCV2604582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1809	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -11.25	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.26	unconstrained · MANE · 10 kb · p 1.8e-07 · regional, not allelic
Overall
CADD	14.27	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 8.48e-05% European (non-Finnish) · 1/1,179,402 alleles

Overall 6.85e-05% 1/1,460,816 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: CYLC2
Protein: p.Lys328Arg
Coding: c.983A>G
MANE Select: NM_001340
dbSNP: rs1354650905
Type: single nucleotide variant
Location: chr9:103005614 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.39
Residue 328: the '31 x 3 aa repeats of k-k-x' region; the 'disordered' region

Full CYLC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYLC2 p.Lys328Glu Uncertain significance ★ ⚠ same residue
CYLC2 p.Asp330His Uncertain significance ★★ ⚠ same type
CYLC2 p.Ala175Val Uncertain significance ★ ⚠ same type
CYLC2 p.Ala296Thr Uncertain significance ★ ⚠ same type
CYLC2 p.Ala327Glu Uncertain significance ★ ⚠ same type
CYLC2 p.Arg42Gln Uncertain significance ★ ⚠ same type
CYLC2 p.Arg55Gln Uncertain significance ★ ⚠ same type
CYLC2 p.Arg55Trp 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/cylc2-p-lys328arg (accessed [today's date]).

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