Is EHMT1 p.Arg12Met (c.35G>T) pathogenic?

EHMT1 p.Arg12Met (c.35G>T) is classified Benign in EHMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-08). AlphaMissense: likely benign (0.2245); Very rare (popmax 0.00134%, afr); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Arg12Met (c.35G>T)?

EHMT1 p.Arg12Met (c.35G>T) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Arg12Met (c.35G>T) in the general population?

EHMT1 p.Arg12Met (c.35G>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about EHMT1 p.Arg12Met (c.35G>T)?

AlphaMissense predicts likely benign (score 0.2245) — an in-silico prediction, not a clinical call.

EHMT1 p.Arg12Met

c.35G>T · rs777999570 · VCV462996

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2245 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Kleefstra syndrome 1

Computational evidence

Protein change
AlphaMissense	0.2245	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -7.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.3	GERP 0.28, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 144 kb · p 1.3e-07 · regional, not allelic
Overall
CADD	22.4	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 0.00134% African / African-American · 1/74,796 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000415% 6/1,445,226 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,796
European (non-Finnish)	0.000426%	234,544

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.Arg12Met
Coding: c.35G>T
MANE Select: NM_024757
dbSNP: rs777999570
Type: single nucleotide variant
Location: chr9:137710980 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 12: 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.Arg12Lys Benign/Likely benign ★★ same residue
EHMT1 p.Arg12Ser Uncertain significance ★ ⚠ same residue
EHMT1 p.Arg12Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
EHMT1 p.Arg12= Likely benign ★ same residue
EHMT1 p.Arg12fs Pathogenic ★ 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

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-arg12met (accessed [today's date]).

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