Is EHMT1 p.Val224Ala (c.671T>C) pathogenic?

EHMT1 p.Val224Ala (c.671T>C) is classified Uncertain significance in EHMT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-20). AlphaMissense: likely benign (0.0775); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with EHMT1 p.Val224Ala (c.671T>C)?

EHMT1 p.Val224Ala (c.671T>C) is associated with Inborn genetic diseases, Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Val224Ala (c.671T>C) in the general population?

EHMT1 p.Val224Ala (c.671T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EHMT1 p.Val224Ala (c.671T>C)?

AlphaMissense predicts likely benign (score 0.0775) — an in-silico prediction, not a clinical call.

EHMT1 p.Val224Ala

c.671T>C · VCV3274911

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0775 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0775	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -4.57	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 0.46	GERP -2, phastCons 0.055
Regional constraint	o/e 1.20	unconstrained · MANE · 144 kb · p 1.3e-07 · regional, not allelic
Overall
CADD	8.091	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EHMT1
Protein: p.Val224Ala
Coding: c.671T>C
MANE Select: NM_024757
Type: single nucleotide variant
Location: chr9:137728377 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 224: 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.Val224= Likely benign ★★ same residue
EHMT1 p.Val224Ile Conflicting classifications of pathogenicity ★ ⚠ 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
EHMT1 c.2867+2T>C Pathogenic/Likely 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-val224ala (accessed [today's date]).

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