Is YTHDF2 p.Lys548Arg (c.1643A>G) pathogenic?

YTHDF2 p.Lys548Arg (c.1643A>G) is classified Uncertain significance in YTHDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-19). AlphaMissense: likely benign (0.0881); Ultra-rare (popmax 0.0205%, nfe).

How common is YTHDF2 p.Lys548Arg (c.1643A>G) in the general population?

YTHDF2 p.Lys548Arg (c.1643A>G) is ultra-rare (popmax 0.0205%, nfe) (gnomAD).

What do computational predictors say about YTHDF2 p.Lys548Arg (c.1643A>G)?

AlphaMissense predicts likely benign (score 0.0881) — an in-silico prediction, not a clinical call.

YTHDF2 p.Lys548Arg

c.1643A>G · rs367798965 · VCV2353752

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0881 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0205%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0881	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -3.56	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 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 25 kb · p 0.0043 · regional, not allelic
Overall
CADD	24.7	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 0.0205% European (non-Finnish) · 241/1,174,308 alleles

Filtering AF 0.0183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0175%

Overall 0.0153% 245/1,598,930 alleles · ultra-rare exomes 231/1,446,698 · genomes 14/152,232 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0205%	4,873
Remaining individualsnot grpmax-eligible	0.00485%	20,611
African / African-American	0.00135%	74,190

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.Lys548Arg
Coding: c.1643A>G
MANE Select: NM_016258
dbSNP: rs367798965
Type: single nucleotide variant
Location: chr1:28743913 (GRCh38)
Gene constraint: LOEUF 0.132 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.14 · 29 PDB
Residue 548: 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-lys548arg (accessed [today's date]).

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