Is EHMT1 p.Ser729= (c.2187G>A) pathogenic?

EHMT1 p.Ser729= (c.2187G>A) is classified Conflicting classifications of pathogenicity in EHMT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-10-03). Very rare (popmax 0.00549%, sas); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Ser729= (c.2187G>A)?

EHMT1 p.Ser729= (c.2187G>A) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Ser729= (c.2187G>A) in the general population?

EHMT1 p.Ser729= (c.2187G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

EHMT1 p.Ser729=

c.2187G>A · rs753928723 · VCV810485

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Conditions

Kleefstra syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -2.8
Overall
CADD	0.324	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,064 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000744% 12/1,613,698 alleles · very rare exomes 9/1,461,614 · genomes 3/152,084 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,213
Remaining individualsnot grpmax-eligible	0.0032%	31,241
African / African-American	0.00267%	37,440
European (non-Finnish)	0.000254%	393,345

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.Ser729=
Coding: c.2187G>A
MANE Select: NM_024757
dbSNP: rs753928723
Type: single nucleotide variant
Location: chr9:137778050 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB

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.Ser729Leu 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-ser729 (accessed [today's date]).

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