Is CYLC2 p.Asp330Tyr (c.988G>T) pathogenic?

CYLC2 p.Asp330Tyr (c.988G>T) is classified Uncertain significance in CYLC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-03). AlphaMissense: likely benign (0.2379); Ultra-rare (popmax 0.0402%, eas).

How common is CYLC2 p.Asp330Tyr (c.988G>T) in the general population?

CYLC2 p.Asp330Tyr (c.988G>T) is ultra-rare (popmax 0.0402%, eas) (gnomAD).

What do computational predictors say about CYLC2 p.Asp330Tyr (c.988G>T)?

AlphaMissense predicts likely benign (score 0.2379) — an in-silico prediction, not a clinical call.

CYLC2 p.Asp330Tyr

c.988G>T · rs185998342 · VCV2329112

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2379 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0402%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2379	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -11.80	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 1.2	GERP -0.62, phastCons 0.004
Regional constraint	o/e 1.26	unconstrained · MANE · 10 kb · p 1.8e-07 · regional, not allelic
Overall
CADD	11.25	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 0.0402% East Asian · 18/44,820 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00664% 107/1,610,850 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.132%	760
East Asiangrpmax	0.0402%	2,490
Admixed American	0.01%	9,955
South Asian	0.0011%	90,986

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp330Tyr
Coding: c.988G>T
MANE Select: NM_001340
dbSNP: rs185998342
Type: single nucleotide variant
Location: chr9:103005619 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.39
Residue 330: 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.Asp330His Uncertain significance ★★ ⚠ same residue
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
CYLC2 p.Arg71Gly 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-asp330tyr (accessed [today's date]).

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