Is CDYL2 p.Pro41Leu (c.122C>T) pathogenic?

CDYL2 p.Pro41Leu (c.122C>T) is classified Uncertain significance in CDYL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-24). AlphaMissense: likely pathogenic (0.9929); Very rare (popmax 0.00167%, amr).

How common is CDYL2 p.Pro41Leu (c.122C>T) in the general population?

CDYL2 p.Pro41Leu (c.122C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CDYL2 p.Pro41Leu (c.122C>T)?

AlphaMissense predicts likely pathogenic (score 0.9929) — an in-silico prediction, not a clinical call.

CDYL2 p.Pro41Leu

c.122C>T · rs1260993441 · VCV2385788

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9929	likely pathogenic
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -13.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 183 kb · p 0.014 · regional, not allelic
Overall
CADD	30.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/60,020 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00041% 6/1,461,882 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
African / African-American	0.00133%	75,018
European (non-Finnish)	0.000339%	295,009

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: CDYL2
Protein: p.Pro41Leu
Coding: c.122C>T
MANE Select: NM_152342
dbSNP: rs1260993441
Type: single nucleotide variant
Location: chr16:80685032 (GRCh38)
Gene constraint: LOEUF 0.713 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.08 · 8 PDB
Residue 41: the chromo domain; a β-strand

Full CDYL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDYL2 p.Gly355= Benign ★★ same type
CDYL2 p.Thr261= Benign ★★ same type
CDYL2 p.Ala114Gly Uncertain significance ★ ⚠ same type
CDYL2 p.Ala114Thr Uncertain significance ★ ⚠ same type
CDYL2 p.Ala286Val Uncertain significance ★ ⚠ same type
CDYL2 p.Ala334Thr Uncertain significance ★ ⚠ same type
CDYL2 p.Ala341Gly Uncertain significance ★ ⚠ same type
CDYL2 p.Ala362Thr 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/cdyl2-p-pro41leu (accessed [today's date]).

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