Is EHMT1 p.Ala63Val (c.188C>T) pathogenic?

EHMT1 p.Ala63Val (c.188C>T) is classified Conflicting classifications of pathogenicity in EHMT1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.0853); Ultra-rare (popmax 0.0143%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EHMT1 p.Ala63Val (c.188C>T)?

EHMT1 p.Ala63Val (c.188C>T) is associated with Inborn genetic diseases, Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Ala63Val (c.188C>T) in the general population?

EHMT1 p.Ala63Val (c.188C>T) is ultra-rare (popmax 0.0143%, nfe) (gnomAD).

What do computational predictors say about EHMT1 p.Ala63Val (c.188C>T)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

EHMT1 p.Ala63Val

c.188C>T · rs138292762 · VCV283420

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -6.49	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 1.3	GERP -1.7, phastCons 0.34
Regional constraint	o/e 1.20	unconstrained · MANE · 144 kb · p 1.3e-07 · regional, not allelic
Overall
CADD	13.54	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 0.0143% European (non-Finnish) · 169/1,179,302 alleles

Filtering AF 0.0125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.0107% 173/1,612,238 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0143%	6,978
Remaining individualsnot grpmax-eligible	0.00481%	20,803
East Asian	0.00223%	44,890

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.Ala63Val
Coding: c.188C>T
MANE Select: NM_024757
dbSNP: rs138292762
Type: single nucleotide variant
Location: chr9:137716728 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 63: the 'disordered' region

Full EHMT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Kleefstra syndrome 1

Similar variants

EHMT1 p.Ala63Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
EHMT1 p.Ala63Thr Uncertain significance ★ ⚠ same residue
EHMT1 p.Ala63= 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-ala63val (accessed [today's date]).

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