Is EHMT1 p.Ser166Arg (c.498C>G) pathogenic?

EHMT1 p.Ser166Arg (c.498C>G) is classified Benign in EHMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-12). AlphaMissense: likely benign (0.2795); Very rare (popmax 0.000255%, nfe); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Ser166Arg (c.498C>G)?

EHMT1 p.Ser166Arg (c.498C>G) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Ser166Arg (c.498C>G) in the general population?

EHMT1 p.Ser166Arg (c.498C>G) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about EHMT1 p.Ser166Arg (c.498C>G)?

AlphaMissense predicts likely benign (score 0.2795) — an in-silico prediction, not a clinical call.

EHMT1 p.Ser166Arg

c.498C>G · VCV3679956

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2795 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Kleefstra syndrome 1

Computational evidence

Protein change
AlphaMissense	0.2795	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -7.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -3.8
Regional constraint	o/e 1.20	unconstrained · MANE · 144 kb · p 1.3e-07 · regional, not allelic
Overall
CADD	13.42	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000255% European (non-Finnish) · 3/1,175,596 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000249% 4/1,606,600 alleles · very rare exomes 4/1,454,348 · genomes 0/152,252 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0016%	62,620
European (non-Finnish)grpmax	0.000255%	391,865

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser166Arg
Coding: c.498C>G
MANE Select: NM_024757
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.Ser166= Likely 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-ser166arg (accessed [today's date]).

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