Is YTHDF2 p.Ser143Cys (c.428C>G) pathogenic?

YTHDF2 p.Ser143Cys (c.428C>G) is classified Uncertain significance in YTHDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely benign (0.1988); Very rare (popmax 0.00133%, afr).

How common is YTHDF2 p.Ser143Cys (c.428C>G) in the general population?

YTHDF2 p.Ser143Cys (c.428C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about YTHDF2 p.Ser143Cys (c.428C>G)?

AlphaMissense predicts likely benign (score 0.1988) — an in-silico prediction, not a clinical call.

YTHDF2 p.Ser143Cys

c.428C>G · VCV4606272

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1988	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -10.98	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.35, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 6,311 bp · p 3.2e-05 · regional, not allelic
Overall
CADD	28.4	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

Grpmax group 0.00133% African / African-American · 1/75,024 alleles

Overall 0.000124% 2/1,614,158 alleles · very rare exomes 2/1,461,884 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,024
European (non-Finnish)	8.47e-05%	1,180,045

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.Ser143Cys
Coding: c.428C>G
MANE Select: NM_016258
Type: single nucleotide variant
Location: chr1:28742698 (GRCh38)
Gene constraint: LOEUF 0.132 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.14 · 29 PDB
Residue 143: the 'localization to mrna processing bodies (p-bodies)' 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-ser143cys (accessed [today's date]).

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