Is EHMT1 p.Ser1069Phe (c.3206C>T) pathogenic?

EHMT1 p.Ser1069Phe (c.3206C>T) is classified Benign in EHMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-03). AlphaMissense: ambiguous (0.5614); Very rare (popmax 0.000339%, nfe); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Ser1069Phe (c.3206C>T)?

EHMT1 p.Ser1069Phe (c.3206C>T) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Ser1069Phe (c.3206C>T) in the general population?

EHMT1 p.Ser1069Phe (c.3206C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about EHMT1 p.Ser1069Phe (c.3206C>T)?

AlphaMissense predicts ambiguous (score 0.5614) — an in-silico prediction, not a clinical call.

EHMT1 p.Ser1069Phe

c.3206C>T · rs1477930903 · VCV2120212

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Kleefstra syndrome 1

Computational evidence

Protein change
AlphaMissense	0.5614	ambiguous
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -10.58	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	27.0	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 0.000339% European (non-Finnish) · 4/1,180,030 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,458,270 alleles · very rare

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.Ser1069Phe
Coding: c.3206C>T
MANE Select: NM_024757
dbSNP: rs1477930903
Type: single nucleotide variant
Location: chr9:137814456 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 1069: the pre-set domain

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.Ser1069Tyr Uncertain significance ★ ⚠ 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
EHMT1 c.3036-1G>A 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-ser1069phe (accessed [today's date]).

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