Is EHMT1 p.Ser76= (c.228C>T) pathogenic?

EHMT1 p.Ser76= (c.228C>T) is classified Likely benign in EHMT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-28). Ultra-rare (popmax 0.0164%, mid); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Ser76= (c.228C>T)?

EHMT1 p.Ser76= (c.228C>T) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Ser76= (c.228C>T) in the general population?

EHMT1 p.Ser76= (c.228C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

EHMT1 p.Ser76=

c.228C>T · rs368743632 · VCV1147981

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.032	GERP -1.8
Overall
CADD	7.857	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,080 alleles

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

Overall 0.0013% 21/1,612,918 alleles · ultra-rare exomes 17/1,460,824 · genomes 4/152,094 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
South Asian	0.00549%	18,219
East Asian	0.00445%	22,449
Remaining individualsnot grpmax-eligible	0.0016%	62,460
African / African-American	0.00134%	74,872
European (non-Finnish)	0.000932%	107,255

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.Ser76=
Coding: c.228C>T
MANE Select: NM_024757
dbSNP: rs368743632
Type: single nucleotide variant
Location: chr9:137716768 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 76: 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 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
EHMT1 c.3259-1G>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-ser76 (accessed [today's date]).

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