Is EHMT1 p.Pro130Ser (c.388C>T) pathogenic?

EHMT1 p.Pro130Ser (c.388C>T) is classified Conflicting classifications of pathogenicity in EHMT1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-31). AlphaMissense: likely benign (0.07); Very rare (popmax 0.00446%, eas); Associated with EHMT1-related disorder.

What condition is associated with EHMT1 p.Pro130Ser (c.388C>T)?

EHMT1 p.Pro130Ser (c.388C>T) is associated with EHMT1-related disorder, Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Pro130Ser (c.388C>T) in the general population?

EHMT1 p.Pro130Ser (c.388C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about EHMT1 p.Pro130Ser (c.388C>T)?

AlphaMissense predicts likely benign (score 0.07) — an in-silico prediction, not a clinical call.

EHMT1 p.Pro130Ser

c.388C>T · rs562411087 · VCV1943198

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.07 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EHMT1-related disorder

Computational evidence

Protein change
AlphaMissense	0.07	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -5.92	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 -0.34	GERP -2.4
Regional constraint	o/e 1.20	unconstrained · MANE · 144 kb · p 1.3e-07 · regional, not allelic
Overall
CADD	11.66	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 0.00446% East Asian · 2/44,882 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00031% 5/1,612,976 alleles · very rare exomes 3/1,460,682 · genomes 2/152,294 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,441
African / African-American	0.00267%	37,516
Admixed American	0.00167%	60,000

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.Pro130Ser
Coding: c.388C>T
MANE Select: NM_024757
dbSNP: rs562411087
Type: single nucleotide variant
Location: chr9:137716928 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB

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

Disease context

EHMT1-related disorder

Also linked: Kleefstra syndrome 1

Similar variants

EHMT1 p.Pro130= Benign/Likely benign ★★ same residue
EHMT1 p.Pro130Leu Likely benign ★★ same residue
EHMT1 p.Pro130_Leu132del Likely benign ★ same residue
EHMT1 p.Pro130Ala 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

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-pro130ser (accessed [today's date]).

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