Is YTHDC1 p.Ser334Leu (c.1001C>T) pathogenic?

YTHDC1 p.Ser334Leu (c.1001C>T) is classified Uncertain significance in YTHDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: ambiguous (0.4361); Very rare (popmax 0.00439%, sas).

How common is YTHDC1 p.Ser334Leu (c.1001C>T) in the general population?

YTHDC1 p.Ser334Leu (c.1001C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about YTHDC1 p.Ser334Leu (c.1001C>T)?

AlphaMissense predicts ambiguous (score 0.4361) — an in-silico prediction, not a clinical call.

YTHDC1 p.Ser334Leu

c.1001C>T · VCV3471825

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4361 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4361	ambiguous
REVEL	0.238	benign-leaning
SaProt	LLR -8.63	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 9,141 bp · p 1.4e-17 · regional, not allelic
Overall
CADD	33.0	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 0.00439% South Asian · 4/91,034 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000248% 4/1,613,290 alleles · very rare exomes 4/1,461,052 · genomes 0/152,238 · 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.Ser334Leu
Coding: c.1001C>T
MANE Select: NM_001031732
Type: single nucleotide variant
Location: chr4:68332820 (GRCh38)
Gene constraint: LOEUF 0.184 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.41 · 109 PDB
Residue 334: 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-ser334leu (accessed [today's date]).

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