Is YTHDF1 p.Pro231Leu (c.692C>T) pathogenic?

YTHDF1 p.Pro231Leu (c.692C>T) is classified Uncertain significance in YTHDF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-16). AlphaMissense: ambiguous (0.4197); Ultra-rare (popmax 0.0356%, eas).

How common is YTHDF1 p.Pro231Leu (c.692C>T) in the general population?

YTHDF1 p.Pro231Leu (c.692C>T) is ultra-rare (popmax 0.0356%, eas) (gnomAD).

What do computational predictors say about YTHDF1 p.Pro231Leu (c.692C>T)?

AlphaMissense predicts ambiguous (score 0.4197) — an in-silico prediction, not a clinical call.

YTHDF1 p.Pro231Leu

c.692C>T · VCV3818103

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4197 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, eas)

Computational evidence

Protein change
AlphaMissense	0.4197	ambiguous
REVEL	0.367	indeterminate
SaProt	LLR -12.89	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.25 · regional, not allelic
Overall
CADD	28.7	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 0.0356% East Asian · 16/44,904 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00204% 33/1,613,810 alleles · ultra-rare exomes 31/1,461,596 · genomes 2/152,214 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0356%	2,806
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00133%	74,930
South Asian	0.0011%	91,084
European (non-Finnish)	0.00102%	98,338

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.Pro231Leu
Coding: c.692C>T
MANE Select: NM_017798
Type: single nucleotide variant
Location: chr20:63203248 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 62.83 · 10 PDB

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-pro231leu (accessed [today's date]).

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