Is EHMT1 p.Arg387Cys (c.1159C>T) pathogenic?

EHMT1 p.Arg387Cys (c.1159C>T) is classified Conflicting classifications of pathogenicity in EHMT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0841); Ultra-rare (popmax 0.0401%, eas); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Arg387Cys (c.1159C>T)?

EHMT1 p.Arg387Cys (c.1159C>T) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Arg387Cys (c.1159C>T) in the general population?

EHMT1 p.Arg387Cys (c.1159C>T) is ultra-rare (popmax 0.0401%, eas) (gnomAD).

What do computational predictors say about EHMT1 p.Arg387Cys (c.1159C>T)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

EHMT1 p.Arg387Cys

c.1159C>T · rs532880924 · VCV198259

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Kleefstra syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -7.68	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 3.9	GERP 1.5, phastCons 0.24
Regional constraint	o/e 1.20	unconstrained · MANE · 144 kb · p 1.3e-07 · regional, not allelic
Overall
CADD	19.48	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 0.0401% East Asian · 18/44,886 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0213%

Overall 0.00186% 30/1,614,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0401%	2,494
African / African-American	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0032%	31,254
Admixed American	0.00167%	60,016
European (non-Finnish)	0.000339%	295,010

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.Arg387Cys
Coding: c.1159C>T
MANE Select: NM_024757
dbSNP: rs532880924
Type: single nucleotide variant
Location: chr9:137744079 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 387: 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.Arg387His Conflicting classifications of pathogenicity ★ ⚠ same residue
EHMT1 p.Arg387= 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
EHMT1 c.2712+1G>A Pathogenic ★★ same condition
EHMT1 c.2867+2T>C 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-arg387cys (accessed [today's date]).

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