Is EHMT1 p.Pro252Arg (c.755C>G) pathogenic?

EHMT1 p.Pro252Arg (c.755C>G) is classified Conflicting classifications of pathogenicity in EHMT1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-12-13). AlphaMissense: likely benign (0.1336); Very rare (popmax 0.00167%, amr); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Pro252Arg (c.755C>G)?

EHMT1 p.Pro252Arg (c.755C>G) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Pro252Arg (c.755C>G) in the general population?

EHMT1 p.Pro252Arg (c.755C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about EHMT1 p.Pro252Arg (c.755C>G)?

AlphaMissense predicts likely benign (score 0.1336) — an in-silico prediction, not a clinical call.

EHMT1 p.Pro252Arg

c.755C>G · rs775614771 · VCV573446

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1336 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Kleefstra syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1336	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -7.12	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 5.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 144 kb · p 1.3e-07 · regional, not allelic
Overall
CADD	23.9	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 0.00167% Admixed American · 1/60,012 alleles

Overall 0.000274% 4/1,461,776 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,012
Finnishnot grpmax-eligible	0.00156%	64,036
South Asian	0.0011%	91,070
European (non-Finnish)	8.47e-05%	1,179,944

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.Pro252Arg
Coding: c.755C>G
MANE Select: NM_024757
dbSNP: rs775614771
Type: single nucleotide variant
Location: chr9:137728461 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB

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.Pro252His Conflicting classifications of pathogenicity ★ ⚠ same residue
EHMT1 p.Pro252Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
EHMT1 p.Pro252= Likely benign ★ same residue
EHMT1 p.Pro252Ser 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-pro252arg (accessed [today's date]).

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