Is YTHDF1 p.Asp498Glu (c.1494C>A) pathogenic?

YTHDF1 p.Asp498Glu (c.1494C>A) is classified Uncertain significance in YTHDF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-16). AlphaMissense: likely benign (0.2814); Very rare (popmax 0.00133%, afr).

How common is YTHDF1 p.Asp498Glu (c.1494C>A) in the general population?

YTHDF1 p.Asp498Glu (c.1494C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about YTHDF1 p.Asp498Glu (c.1494C>A)?

AlphaMissense predicts likely benign (score 0.2814) — an in-silico prediction, not a clinical call.

YTHDF1 p.Asp498Glu

c.1494C>A · VCV3333745

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2814 · 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	0.2814	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -4.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 6,103 bp · p 6.2e-10 · regional, not allelic
Overall
CADD	17.08	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 · 1/74,952 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000805% 13/1,614,152 alleles · very rare exomes 12/1,461,890 · genomes 1/152,262 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,952
European (non-Finnish)	0.00102%	98,337

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.Asp498Glu
Coding: c.1494C>A
MANE Select: NM_017798
Type: single nucleotide variant
Location: chr20:63202446 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 62.83 · 10 PDB
Residue 498: the yth domain

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-asp498glu (accessed [today's date]).

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