Is CYLC2 p.Ala34Ser (c.100G>T) pathogenic?

CYLC2 p.Ala34Ser (c.100G>T) is classified Likely benign in CYLC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-12). AlphaMissense: likely benign (0.1022); Ultra-rare (popmax 0.0347%, afr).

How common is CYLC2 p.Ala34Ser (c.100G>T) in the general population?

CYLC2 p.Ala34Ser (c.100G>T) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about CYLC2 p.Ala34Ser (c.100G>T)?

AlphaMissense predicts likely benign (score 0.1022) — an in-silico prediction, not a clinical call.

CYLC2 p.Ala34Ser

c.100G>T · rs80140014 · VCV2283423

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1022 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1022	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -4.99	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 0.68	GERP -3.8, phastCons 1
Regional constraint	o/e 1.26	unconstrained · MANE · 10 kb · p 1.8e-07 · regional, not allelic
Overall
CADD	13.63	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 0.0347% African / African-American · 26/74,898 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00167% 27/1,613,588 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,881
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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.Ala34Ser
Coding: c.100G>T
MANE Select: NM_001340
dbSNP: rs80140014
Type: single nucleotide variant
Location: chr9:103003183 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.39
Residue 34: the '31 x 3 aa repeats of k-k-x' 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-ala34ser (accessed [today's date]).

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