Is YTHDC1 p.Lys9Glu (c.25A>G) pathogenic?

YTHDC1 p.Lys9Glu (c.25A>G) is classified Uncertain significance in YTHDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.3163); Very rare (popmax 8.49e-05%, nfe).

How common is YTHDC1 p.Lys9Glu (c.25A>G) in the general population?

YTHDC1 p.Lys9Glu (c.25A>G) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about YTHDC1 p.Lys9Glu (c.25A>G)?

AlphaMissense predicts likely benign (score 0.3163) — an in-silico prediction, not a clinical call.

YTHDC1 p.Lys9Glu

c.25A>G · rs1725882409 · VCV3191639

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3163	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -4.49	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 7.5	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.93 · regional, not allelic
Overall
CADD	25.0	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 8.49e-05% European (non-Finnish) · 1/1,178,328 alleles

Overall 6.22e-05% 1/1,608,602 alleles · very rare exomes 1/1,460,590 · genomes 0/148,012 · joint denominator

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: YTHDC1
Protein: p.Lys9Glu
Coding: c.25A>G
MANE Select: NM_001031732
dbSNP: rs1725882409
Type: single nucleotide variant
Location: chr4:68349729 (GRCh38)
Gene constraint: LOEUF 0.184 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.41 · 109 PDB
Residue 9: the 'disordered' region

Full YTHDC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

YTHDC1 p.Arg113Gln Uncertain significance ★ ⚠ same type
YTHDC1 p.Arg136Gln Uncertain significance ★ ⚠ same type
YTHDC1 p.Arg301Ser Uncertain significance ★ ⚠ same type
YTHDC1 p.Arg341Gln Uncertain significance ★ ⚠ same type
YTHDC1 p.Arg522His Uncertain significance ★ ⚠ same type
YTHDC1 p.Arg526Gly Uncertain significance ★ ⚠ same type
YTHDC1 p.Arg535Cys Uncertain significance ★ ⚠ same type
YTHDC1 p.Arg560Gly 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/ythdc1-p-lys9glu (accessed [today's date]).

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