Is CYLC2 p.Ala175Val (c.524C>T) pathogenic?

CYLC2 p.Ala175Val (c.524C>T) is classified Uncertain significance in CYLC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-28). AlphaMissense: likely benign (0.1274); Low-frequency (popmax 1.71%, mid).

How common is CYLC2 p.Ala175Val (c.524C>T) in the general population?

CYLC2 p.Ala175Val (c.524C>T) is low-frequency (popmax 1.71%, mid) (gnomAD).

What do computational predictors say about CYLC2 p.Ala175Val (c.524C>T)?

AlphaMissense predicts likely benign (score 0.1274) — an in-silico prediction, not a clinical call.

CYLC2 p.Ala175Val

c.524C>T · rs149924620 · VCV2300096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1274 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.71%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1274	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -8.67	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 -20	GERP -3.8
Regional constraint	o/e 1.26	unconstrained · MANE · 10 kb · p 1.8e-07 · regional, not allelic
Overall
CADD	0.006	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 1.71% Middle Eastern · 102/5,982 alleles

Filtering AF 1.44% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.34%

Overall 0.0387% 621/1,605,156 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.71%	59
South Asian	0.079%	1,266
Remaining individualsnot grpmax-eligible	0.0775%	1,291
Admixed American	0.0626%	1,599
Ashkenazi Jewishnot grpmax-eligible	0.0309%	3,236
European (non-Finnish)	0.0291%	3,434
African / African-American	0.0122%	8,192
Finnishnot grpmax-eligible	0.00472%	21,183

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.Ala175Val
Coding: c.524C>T
MANE Select: NM_001340
dbSNP: rs149924620
Type: single nucleotide variant
Location: chr9:103005155 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.39
Residue 175: the '31 x 3 aa repeats of k-k-x' region; the 'disordered' region; the '3 x approximate tandem repeats' 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.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
CYLC2 p.Arg83Gly 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-ala175val (accessed [today's date]).

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