Is YTHDC1 p.Glu249del (c.690GGA[3]) pathogenic?

YTHDC1 p.Glu249del (c.690GGA[3]) is classified Likely benign in YTHDC1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-04-25). Rare (popmax 0.338%, nfe); Associated with YTHDC1-related disorder.

What condition is associated with YTHDC1 p.Glu249del (c.690GGA[3])?

YTHDC1 p.Glu249del (c.690GGA[3]) is associated with YTHDC1-related disorder (ClinVar).

How common is YTHDC1 p.Glu249del (c.690GGA[3]) in the general population?

YTHDC1 p.Glu249del (c.690GGA[3]) is rare (popmax 0.338%, nfe) (gnomAD).

YTHDC1 p.Glu249del

c.690GGA[3] · rs566379464 · VCV3053679

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.338%, nfe)

Conditions

YTHDC1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.3
Overall
CADD	15.7	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(TCC)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.338% European (non-Finnish) · 3,920/1,158,572 alleles

Filtering AF 0.329% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.326%

Overall 0.289% 4,593/1,589,110 alleles · rare exomes 4,195/1,437,226 · genomes 398/151,884 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.604%	165
European (non-Finnish)grpmax	0.338%	296
Remaining individualsnot grpmax-eligible	0.188%	531
Admixed American	0.153%	655
Ashkenazi Jewishnot grpmax-eligible	0.0544%	1,837
Middle Eastern	0.0497%	2,011
African / African-American	0.039%	2,566
South Asian	0.0344%	2,910
East Asian	0.00448%	22,315

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu249del
Coding: c.690GGA[3]
MANE Select: NM_001031732
dbSNP: rs566379464
Type: Microsatellite
Location: chr4:68337209 (GRCh38)
Gene constraint: LOEUF 0.184 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.41 · 109 PDB
Residue 249: the 'disordered' region

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

Disease context

YTHDC1-related disorder

Similar variants

YTHDC1 p.Glu249Ala Uncertain significance ★ ⚠ same residue

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-glu249del (accessed [today's date]).

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