Is EHMT1 p.Ser146= (c.438G>A) pathogenic?

EHMT1 p.Ser146= (c.438G>A) is classified Likely benign in EHMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-15). Ultra-rare (popmax 0.0461%, sas); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Ser146= (c.438G>A)?

EHMT1 p.Ser146= (c.438G>A) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Ser146= (c.438G>A) in the general population?

EHMT1 p.Ser146= (c.438G>A) is ultra-rare (popmax 0.0461%, sas) (gnomAD).

EHMT1 p.Ser146=

c.438G>A · rs151008340 · VCV365996

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0461%, 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 -6.6	GERP -3.8
Overall
CADD	0.805	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0461% South Asian · 42/91,066 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.0142% 229/1,610,130 alleles · ultra-rare exomes 216/1,457,948 · genomes 13/152,182 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0461%	2,168
Remaining individualsnot grpmax-eligible	0.0257%	3,899
European (non-Finnish)	0.0139%	7,181
East Asian	0.0067%	14,935
Admixed American	0.00501%	19,969
African / African-American	0.00134%	74,894

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.Ser146=
Coding: c.438G>A
MANE Select: NM_024757
dbSNP: rs151008340
Type: single nucleotide variant
Location: chr9:137716978 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 146: 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.Ser146Leu 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-ser146 (accessed [today's date]).

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