Is EHMT1 p.Arg78Ser (c.234G>C) pathogenic?

EHMT1 p.Arg78Ser (c.234G>C) is classified Benign in EHMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-03). AlphaMissense: likely benign (0.165); Very rare (popmax 0.004%, afr); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Arg78Ser (c.234G>C)?

EHMT1 p.Arg78Ser (c.234G>C) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Arg78Ser (c.234G>C) in the general population?

EHMT1 p.Arg78Ser (c.234G>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about EHMT1 p.Arg78Ser (c.234G>C)?

AlphaMissense predicts likely benign (score 0.165) — an in-silico prediction, not a clinical call.

EHMT1 p.Arg78Ser

c.234G>C · rs1054853293 · VCV576294

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.165 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Kleefstra syndrome 1

Computational evidence

Protein change
AlphaMissense	0.165	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -4.55	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 -0.15	GERP -3.8
Regional constraint	o/e 1.20	unconstrained · MANE · 144 kb · p 1.3e-07 · regional, not allelic
Overall
CADD	2.362	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 0.004% African / African-American · 3/74,980 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000274% 4/1,460,814 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,993
European (non-Finnish)	8.48e-05%	1,179,805

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.Arg78Ser
Coding: c.234G>C
MANE Select: NM_024757
dbSNP: rs1054853293
Type: single nucleotide variant
Location: chr9:137716774 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 78: 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.Arg78Thr Uncertain significance ★★ ⚠ same residue
EHMT1 p.Arg78Lys Uncertain significance ★ ⚠ same residue
EHMT1 p.Arg78Met 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

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-arg78ser (accessed [today's date]).

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