Is YTHDF1 p.Val511Leu (c.1531G>C) pathogenic?

YTHDF1 p.Val511Leu (c.1531G>C) is classified Uncertain significance in YTHDF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-16). AlphaMissense: likely pathogenic (0.9696); Very rare (popmax 8.47e-05%, nfe).

How common is YTHDF1 p.Val511Leu (c.1531G>C) in the general population?

YTHDF1 p.Val511Leu (c.1531G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about YTHDF1 p.Val511Leu (c.1531G>C)?

AlphaMissense predicts likely pathogenic (score 0.9696) — an in-silico prediction, not a clinical call.

YTHDF1 p.Val511Leu

c.1531G>C · VCV3333749

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9696 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9696	likely pathogenic
REVEL	0.334	indeterminate
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 6,103 bp · p 6.2e-10 · regional, not allelic
Overall
CADD	24.3	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 8.47e-05% European (non-Finnish) · 1/1,180,062 alleles

Overall 6.2e-05% 1/1,614,160 alleles · very rare exomes 0/1,461,894 · genomes 1/152,266 · 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: YTHDF1
Protein: p.Val511Leu
Coding: c.1531G>C
MANE Select: NM_017798
Type: single nucleotide variant
Location: chr20:63202409 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 62.83 · 10 PDB
Residue 511: the yth domain; a β-strand

Full YTHDF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

YTHDF1 p.Asn497= Benign ★★ same type
YTHDF1 p.His375Tyr Benign ★★ same type
YTHDF1 p.Lys473= Benign ★★ same type
YTHDF1 p.Ser145= Benign ★★ same type
YTHDF1 p.Ser252= Benign ★★ same type
YTHDF1 p.Val195= Benign ★★ same type
YTHDF1 p.Ala146Thr Uncertain significance ★ ⚠ same type
YTHDF1 p.Ala199Ser 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/ythdf1-p-val511leu (accessed [today's date]).

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