Is EHMT1 p.Ser453= (c.1359C>T) pathogenic?

EHMT1 p.Ser453= (c.1359C>T) is classified Benign/Likely benign in EHMT1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-11). Rare (popmax 0.121%, sas); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Ser453= (c.1359C>T)?

EHMT1 p.Ser453= (c.1359C>T) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Ser453= (c.1359C>T) in the general population?

EHMT1 p.Ser453= (c.1359C>T) is rare (popmax 0.121%, sas) (gnomAD).

EHMT1 p.Ser453=

c.1359C>T · rs545055517 · VCV708189

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.121%, sas)

Conditions

Kleefstra syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.6	GERP -1.9
Overall
CADD	9.033	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.121% South Asian · 110/91,072 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0956%

Overall 0.0141% 227/1,613,950 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.121%	828
Middle Eastern	0.0496%	2,018
Admixed American	0.0183%	5,456
Remaining individualsnot grpmax-eligible	0.0176%	5,681
European (non-Finnish)	0.00771%	12,966
East Asian	0.00223%	44,880

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: EHMT1
Protein: p.Ser453=
Coding: c.1359C>T
MANE Select: NM_024757
dbSNP: rs545055517
Type: single nucleotide variant
Location: chr9:137754281 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 453: the 'disordered' region

Full EHMT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Kleefstra syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EHMT1 p.Ser453Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
EHMT1 c.1370-1G>C Likely pathogenic ★★ same condition
EHMT1 c.1647+2T>C Pathogenic/Likely pathogenic ★★ same condition
EHMT1 c.2193-1G>C Pathogenic ★★ same condition
EHMT1 c.2276-2A>G Pathogenic ★★ same condition
EHMT1 c.2712+1G>A Pathogenic ★★ same condition
EHMT1 c.2867+2T>C Pathogenic/Likely pathogenic ★★ same condition
EHMT1 c.3036-1G>A Pathogenic/Likely 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/ehmt1-p-ser453 (accessed [today's date]).

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