Is EMSY p.Val754Ala (c.2261T>C) pathogenic?

EMSY p.Val754Ala (c.2261T>C) is classified Likely benign in EMSY (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-03-16). AlphaMissense: likely pathogenic (0.8114); Rare (popmax 0.25%, eas); Associated with EMSY-related disorder.

What condition is associated with EMSY p.Val754Ala (c.2261T>C)?

EMSY p.Val754Ala (c.2261T>C) is associated with EMSY-related disorder (ClinVar).

How common is EMSY p.Val754Ala (c.2261T>C) in the general population?

EMSY p.Val754Ala (c.2261T>C) is rare (popmax 0.25%, eas) (gnomAD).

What do computational predictors say about EMSY p.Val754Ala (c.2261T>C)?

AlphaMissense predicts likely pathogenic (score 0.8114) — an in-silico prediction, not a clinical call.

EMSY p.Val754Ala

c.2261T>C · rs569041290 · VCV3030378

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8114 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.25%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EMSY-related disorder

Computational evidence

Protein change
AlphaMissense	0.8114	likely pathogenic
REVEL	0.267	benign-leaning
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Overall
CADD	24.6	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 V739A vs ClinVar V754A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.25% East Asian · 107/42,882 alleles

Filtering AF 0.211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.197%

Overall 0.0071% 110/1,549,036 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.25%	401
Remaining individualsnot grpmax-eligible	0.00507%	19,727

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: EMSY
Protein: p.Val754Ala
Coding: c.2261T>C
MANE Select: NM_001300942
dbSNP: rs569041290
Type: single nucleotide variant
Location: chr11:76535916 (GRCh38)
Gene constraint: LOEUF 0.262 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 42.40 · 3 PDB

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

Disease context

EMSY-related disorder

Similar variants

EMSY c.1730-5C>G Uncertain significance ★ same condition
EMSY p.Gln1260Arg Uncertain significance ★ ⚠ same condition
EMSY c.1559-4G>A Benign same condition
EMSY p.Thr1231= Benign same condition
EMSY c.1730-7T>C Benign/Likely benign ★★ same type
EMSY c.71-7C>T Benign ★★ same type
EMSY p.Arg221= Benign ★★ same type
EMSY p.Gln988= Benign ★★ 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/emsy-p-val754ala (accessed [today's date]).

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