Is CYLC2 p.Asp156Glu (c.468T>A) pathogenic?

CYLC2 p.Asp156Glu (c.468T>A) is classified Uncertain significance in CYLC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-05). AlphaMissense: likely benign (0.1163); Ultra-rare (popmax 0.0432%, sas).

How common is CYLC2 p.Asp156Glu (c.468T>A) in the general population?

CYLC2 p.Asp156Glu (c.468T>A) is ultra-rare (popmax 0.0432%, sas) (gnomAD).

What do computational predictors say about CYLC2 p.Asp156Glu (c.468T>A)?

AlphaMissense predicts likely benign (score 0.1163) — an in-silico prediction, not a clinical call.

CYLC2 p.Asp156Glu

c.468T>A · rs770541890 · VCV2207422

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1163 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0432%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1163	likely benign
REVEL	0.002	strongly benign-leaning
SaProt	LLR -7.09	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 -7.1	GERP -3.7
Regional constraint	o/e 1.26	unconstrained · MANE · 10 kb · p 1.8e-07 · regional, not allelic
Overall
CADD	0.08	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 0.0432% South Asian · 39/90,346 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0287%

Overall 0.00243% 39/1,605,606 alleles · ultra-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.Asp156Glu
Coding: c.468T>A
MANE Select: NM_001340
dbSNP: rs770541890
Type: single nucleotide variant
Location: chr9:103005099 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.39
Residue 156: 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 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
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-asp156glu (accessed [today's date]).

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