Is YTHDF2 p.Asp496Asn (c.1486G>A) pathogenic?

YTHDF2 p.Asp496Asn (c.1486G>A) is classified Uncertain significance in YTHDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-23). AlphaMissense: ambiguous (0.5323); Absent from gnomAD v4.1.

How common is YTHDF2 p.Asp496Asn (c.1486G>A) in the general population?

YTHDF2 p.Asp496Asn (c.1486G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about YTHDF2 p.Asp496Asn (c.1486G>A)?

AlphaMissense predicts ambiguous (score 0.5323) — an in-silico prediction, not a clinical call.

YTHDF2 p.Asp496Asn

c.1486G>A · rs2545347192 · VCV2477251

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5323 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5323	ambiguous
REVEL	0.198	benign-leaning
SaProt	LLR -9.31	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 10	GERP 2.1, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 383 bp · p 2.7e-17 · 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: YTHDF2
Protein: p.Asp496Asn
Coding: c.1486G>A
MANE Select: NM_016258
dbSNP: rs2545347192
Type: single nucleotide variant
Location: chr1:28743756 (GRCh38)
Gene constraint: LOEUF 0.132 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.14 · 29 PDB
Residue 496: the yth domain; a β-strand; the 'interaction with m6a-containing mrnas' region

Full YTHDF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

YTHDF2 p.Ala170Gly Uncertain significance ★ ⚠ same type
YTHDF2 p.Ala285Gly Uncertain significance ★ ⚠ same type
YTHDF2 p.Arg10Lys Uncertain significance ★ ⚠ same type
YTHDF2 p.Arg393Trp Uncertain significance ★ ⚠ same type
YTHDF2 p.Arg574His Uncertain significance ★ ⚠ same type
YTHDF2 p.Gln327Arg Uncertain significance ★ ⚠ same type
YTHDF2 p.Glu8Gln Uncertain significance ★ ⚠ same type
YTHDF2 p.Gly212Arg 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/ythdf2-p-asp496asn (accessed [today's date]).

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