Is CDYL p.Ser138Thr (c.412T>A) pathogenic?

CDYL p.Ser138Thr (c.412T>A) is classified Uncertain significance in CDYL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: likely benign (0.0948); Ultra-rare (popmax 0.0327%, nfe).

How common is CDYL p.Ser138Thr (c.412T>A) in the general population?

CDYL p.Ser138Thr (c.412T>A) is ultra-rare (popmax 0.0327%, nfe) (gnomAD).

What do computational predictors say about CDYL p.Ser138Thr (c.412T>A)?

AlphaMissense predicts likely benign (score 0.0948) — an in-silico prediction, not a clinical call.

CDYL p.Ser138Thr

c.412T>A · rs139710301 · VCV2259852

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0948 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0327%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0948	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -6.94	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 4.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 159 kb · p 0.037 · regional, not allelic
Overall
CADD	20.3	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S192T vs ClinVar S138T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0327% European (non-Finnish) · 386/1,180,030 alleles

Filtering AF 0.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0289%

Overall 0.0254% 410/1,614,036 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0327%	3,057
Admixed American	0.015%	6,667
Remaining individualsnot grpmax-eligible	0.0144%	6,943
African / African-American	0.00401%	24,969
Finnishnot grpmax-eligible	0.00312%	32,013
South Asian	0.0011%	91,086

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: CDYL
Protein: p.Ser138Thr
Coding: c.412T>A
MANE Select: NM_004824
dbSNP: rs139710301
Type: single nucleotide variant
Location: chr6:4892100 (GRCh38)
Gene constraint: LOEUF 0.293 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.33 · 3 PDB
Residue 138: the 'interaction with ezh2' region; the 'disordered' region

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

Similar variants

CDYL p.Ala136Val Uncertain significance ★ ⚠ same type
CDYL p.Ala154Thr Uncertain significance ★ ⚠ same type
CDYL p.Ala182Ser Uncertain significance ★ ⚠ same type
CDYL p.Ala183Val Uncertain significance ★ ⚠ same type
CDYL p.Ala195Thr Uncertain significance ★ ⚠ same type
CDYL p.Ala329Thr Uncertain significance ★ ⚠ same type
CDYL p.Ala527Ser Uncertain significance ★ ⚠ same type
CDYL p.Arg11Lys 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/cdyl-p-ser138thr (accessed [today's date]).

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