Is EHMT1 p.Ser166= (c.498C>T) pathogenic?

EHMT1 p.Ser166= (c.498C>T) is classified Likely benign in EHMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). Ultra-rare (popmax 0.0187%, afr); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Ser166= (c.498C>T)?

EHMT1 p.Ser166= (c.498C>T) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Ser166= (c.498C>T) in the general population?

EHMT1 p.Ser166= (c.498C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

EHMT1 p.Ser166=

c.498C>T · rs146037252 · VCV531874

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

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 -1.6	GERP -3.8
Overall
CADD	9.047	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/74,766 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00906%

Overall 0.00485% 78/1,606,600 alleles · ultra-rare exomes 68/1,454,348 · genomes 10/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,340
European (non-Finnish)	0.0051%	19,593
Remaining individualsnot grpmax-eligible	0.00483%	20,712
Admixed American	0.00168%	59,576

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.Ser166=
Coding: c.498C>T
MANE Select: NM_024757
dbSNP: rs146037252
Type: single nucleotide variant
Location: chr9:137717038 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 166: 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.Ser166Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
EHMT1 p.Ser166Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
EHMT1 p.Ser166Thr Uncertain significance ★ ⚠ same residue
EHMT1 p.Ser166Arg Benign ★ 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

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-ser166 (accessed [today's date]).

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