Is YTHDC1 p.Glu173Asp (c.519A>C) pathogenic?

YTHDC1 p.Glu173Asp (c.519A>C) is classified Uncertain significance in YTHDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-08). AlphaMissense: likely benign (0.1378); Very rare (popmax 0.00712%, nfe).

How common is YTHDC1 p.Glu173Asp (c.519A>C) in the general population?

YTHDC1 p.Glu173Asp (c.519A>C) is very rare (popmax 0.00712%, nfe) (gnomAD).

What do computational predictors say about YTHDC1 p.Glu173Asp (c.519A>C)?

AlphaMissense predicts likely benign (score 0.1378) — an in-silico prediction, not a clinical call.

YTHDC1 p.Glu173Asp

c.519A>C · VCV4203312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1378 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00712%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1378	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -6.61	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 0.032	phastCons 0.95
Regional constraint	o/e 0.94	unconstrained · MANE · 4,938 bp · p 0.3 · regional, not allelic
Overall
CADD	17.14	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 0.00712% European (non-Finnish) · 84/1,180,040 alleles

Filtering AF 0.00588% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00541%

Overall 0.00527% 85/1,614,072 alleles · very rare exomes 80/1,461,864 · genomes 5/152,208 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00712%	14,048
African / African-American	0.00133%	74,928

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.Glu173Asp
Coding: c.519A>C
MANE Select: NM_001031732
Type: single nucleotide variant
Location: chr4:68337391 (GRCh38)
Gene constraint: LOEUF 0.184 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.41 · 109 PDB
Residue 173: 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-glu173asp (accessed [today's date]).

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