Is EHMT1 p.Ala43= (c.129A>G) pathogenic?

EHMT1 p.Ala43= (c.129A>G) is classified Likely benign in EHMT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-01). Very rare (popmax 0.00169%, amr); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Ala43= (c.129A>G)?

EHMT1 p.Ala43= (c.129A>G) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Ala43= (c.129A>G) in the general population?

EHMT1 p.Ala43= (c.129A>G) is very rare (popmax 0.00169%, amr) (gnomAD).

EHMT1 p.Ala43=

c.129A>G · rs76684726 · VCV1112068

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Conditions

Kleefstra syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3.5
Overall
CADD	3.666	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% Admixed American · 1/59,160 alleles

Overall 6.26e-05% 1/1,598,222 alleles · very rare exomes 1/1,446,156 · genomes 0/152,066 · joint denominator

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.Ala43=
Coding: c.129A>G
MANE Select: NM_024757
dbSNP: rs76684726
Type: single nucleotide variant
Location: chr9:137716669 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 43: the 'disordered' region; a UniProt-annotated variant site (in a breast cancer sample; somatic mutation)

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.Ala43Ser Uncertain significance ★★ ⚠ same residue
EHMT1 p.Ala43Thr Uncertain significance ★ ⚠ same residue
EHMT1 p.Ala43Pro Benign ★ same residue
EHMT1 p.Ala43Val Benign ★ same residue
EHMT1 p.Ala43Gly 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

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-ala43 (accessed [today's date]).

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