Is YTHDF1 p.Val224Met (c.670G>A) pathogenic?

YTHDF1 p.Val224Met (c.670G>A) is classified Uncertain significance in YTHDF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely benign (0.0939); Very rare (popmax 0.00133%, afr).

How common is YTHDF1 p.Val224Met (c.670G>A) in the general population?

YTHDF1 p.Val224Met (c.670G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about YTHDF1 p.Val224Met (c.670G>A)?

AlphaMissense predicts likely benign (score 0.0939) — an in-silico prediction, not a clinical call.

YTHDF1 p.Val224Met

c.670G>A · VCV4203348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0939 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0939	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -7.97	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 2.2	GERP -0.19, phastCons 0.98
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.25 · regional, not allelic
Overall
CADD	17.84	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 0.00133% African / African-American · 1/74,942 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,613,796 alleles · very rare exomes 6/1,461,572 · genomes 2/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,942
South Asian	0.0011%	91,088
European (non-Finnish)	0.000508%	196,676

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.Val224Met
Coding: c.670G>A
MANE Select: NM_017798
Type: single nucleotide variant
Location: chr20:63203270 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 62.83 · 10 PDB

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-val224met (accessed [today's date]).

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