Is EHMT1 p.Leu685Pro (c.2054T>C) pathogenic?

EHMT1 p.Leu685Pro (c.2054T>C) is classified Conflicting classifications of pathogenicity in EHMT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-02). AlphaMissense: likely benign (0.0428); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with EHMT1 p.Leu685Pro (c.2054T>C)?

EHMT1 p.Leu685Pro (c.2054T>C) is associated with Inborn genetic diseases (ClinVar).

How common is EHMT1 p.Leu685Pro (c.2054T>C) in the general population?

EHMT1 p.Leu685Pro (c.2054T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about EHMT1 p.Leu685Pro (c.2054T>C)?

AlphaMissense predicts likely benign (score 0.0428) — an in-silico prediction, not a clinical call.

EHMT1 p.Leu685Pro

c.2054T>C · rs1367225717 · VCV2446107

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0428 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0428	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -5.82	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 0.36	GERP -0.66, phastCons 0.099
Regional constraint	o/e 0.97	unconstrained · MANE · 1,208 bp · p 0.79 · regional, not allelic
Overall
CADD	5.69	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 0.0022% South Asian · 2/91,068 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,613,658 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.Leu685Pro
Coding: c.2054T>C
MANE Select: NM_024757
dbSNP: rs1367225717
Type: single nucleotide variant
Location: chr9:137777917 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 685: 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

Similar variants

EHMT1 p.Leu685Met Uncertain significance ★ ⚠ same residue
EHMT1 c.2193-1G>C Pathogenic ★★ same condition
EHMT1 p.Arg1116Ter Pathogenic ★★ same condition
EHMT1 p.Arg291Ter Pathogenic ★★ same condition
EHMT1 p.Arg490Ter Pathogenic/Likely pathogenic ★★ same condition
EHMT1 p.Trp437Ter Pathogenic/Likely pathogenic ★★ same condition
EHMT1 c.3461+3G>A Uncertain significance ★★ same condition
EHMT1 c.-5G>A Uncertain significance ★★ 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-leu685pro (accessed [today's date]).

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