Is YTHDF2 p.Val455Ile (c.1363G>A) pathogenic?

YTHDF2 p.Val455Ile (c.1363G>A) is classified Uncertain significance in YTHDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-27). AlphaMissense: likely benign (0.1084); Very rare (popmax 0.00439%, sas).

How common is YTHDF2 p.Val455Ile (c.1363G>A) in the general population?

YTHDF2 p.Val455Ile (c.1363G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about YTHDF2 p.Val455Ile (c.1363G>A)?

AlphaMissense predicts likely benign (score 0.1084) — an in-silico prediction, not a clinical call.

YTHDF2 p.Val455Ile

c.1363G>A · rs769780788 · VCV2602736

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1084	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -8.09	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 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	26.5	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 0.00439% South Asian · 4/91,080 alleles

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

Overall 0.000682% 11/1,614,020 alleles · very rare exomes 10/1,461,876 · genomes 1/152,144 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000508%	196,672

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: YTHDF2
Protein: p.Val455Ile
Coding: c.1363G>A
MANE Select: NM_016258
dbSNP: rs769780788
Type: single nucleotide variant
Location: chr1:28743633 (GRCh38)
Gene constraint: LOEUF 0.132 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.14 · 29 PDB
Residue 455: 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.Asp496Asn Uncertain significance ★ ⚠ same type
YTHDF2 p.Gln327Arg Uncertain significance ★ ⚠ same type
YTHDF2 p.Glu8Gln 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-val455ile (accessed [today's date]).

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