Is YY1AP1 p.Cys308Ser (c.923G>C) pathogenic?

YY1AP1 p.Cys308Ser (c.923G>C) is classified Uncertain significance in YY1AP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: likely pathogenic (0.8449); Very rare (popmax 0.00988%, sas); Associated with grange syndrome.

What condition is associated with YY1AP1 p.Cys308Ser (c.923G>C)?

YY1AP1 p.Cys308Ser (c.923G>C) is associated with grange syndrome (ClinVar).

How common is YY1AP1 p.Cys308Ser (c.923G>C) in the general population?

YY1AP1 p.Cys308Ser (c.923G>C) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about YY1AP1 p.Cys308Ser (c.923G>C)?

AlphaMissense predicts likely pathogenic (score 0.8449) — an in-silico prediction, not a clinical call.

YY1AP1 p.Cys308Ser

c.923G>C · rs372439408 · VCV3254939

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8449 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

grange syndrome

Computational evidence

Protein change
AlphaMissense	0.8449	likely pathogenic · top 7% in YY1AP1
REVEL	0.32	indeterminate
SaProt	LLR -1.19	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 11 kb · p 0.016 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C354S vs ClinVar C308S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00988% South Asian · 9/91,078 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.000616% 9/1,461,634 alleles · very rare

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: YY1AP1
Protein: p.Cys308Ser
Coding: c.923G>C
MANE Select: NM_139119
dbSNP: rs372439408
Type: single nucleotide variant
Location: chr1:155661380 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.58
Residue 308: a UniProt-annotated variant site (in grng)

Full YY1AP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

grange syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

YY1AP1 c.412-1G>A Pathogenic ★★ same condition
YY1AP1 p.Gln84Ter Pathogenic/Likely pathogenic ★★ same condition
YY1AP1 c.583+23T>G Pathogenic ★ same condition
YY1AP1 p.Arg398Cys Uncertain significance ★ ⚠ same condition
YY1AP1 p.Pro495Leu Uncertain significance ★ ⚠ same condition
YY1AP1 p.Gln104Ter Pathogenic same condition
YY1AP1 p.Glu663Ter Pathogenic same condition
YY1AP1 p.Leu659Ter Pathogenic same condition

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/yy1ap1-p-cys308ser (accessed [today's date]).

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