Is YTHDC1 p.Arg535Cys (c.1603C>T) pathogenic?

YTHDC1 p.Arg535Cys (c.1603C>T) is classified Uncertain significance in YTHDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: likely benign (0.3027); Very rare (popmax 0.00405%, afr).

How common is YTHDC1 p.Arg535Cys (c.1603C>T) in the general population?

YTHDC1 p.Arg535Cys (c.1603C>T) is very rare (popmax 0.00405%, afr) (gnomAD).

What do computational predictors say about YTHDC1 p.Arg535Cys (c.1603C>T)?

AlphaMissense predicts likely benign (score 0.3027) — an in-silico prediction, not a clinical call.

YTHDC1 p.Arg535Cys

c.1603C>T · VCV3471819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00405%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3027	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -11.34	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 10 kb · p 1.4e-09 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00405% African / African-American · 3/74,018 alleles

Filtering AF 0.00108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000498%

Overall 0.001% 16/1,600,536 alleles · very rare exomes 11/1,448,604 · genomes 5/151,932 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00405%	24,673
Ashkenazi Jewishnot grpmax-eligible	0.00342%	29,266
European (non-Finnish)	0.00102%	98,057

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.Arg535Cys
Coding: c.1603C>T
MANE Select: NM_001031732
Type: single nucleotide variant
Location: chr4:68320204 (GRCh38)
Gene constraint: LOEUF 0.184 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.41 · 109 PDB
Residue 535: 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.Arg560Gly Uncertain significance ★ ⚠ same type
YTHDC1 p.Arg59Gln 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-arg535cys (accessed [today's date]).

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