Is EHMT1 p.Pro975Ala (c.2923C>G) pathogenic?

EHMT1 p.Pro975Ala (c.2923C>G) is classified Uncertain significance in EHMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-06). AlphaMissense: ambiguous (0.5344); Very rare (popmax 0.000593%, nfe); Associated with Kleefstra syndrome 1.

What condition is associated with EHMT1 p.Pro975Ala (c.2923C>G)?

EHMT1 p.Pro975Ala (c.2923C>G) is associated with Kleefstra syndrome 1 (ClinVar).

How common is EHMT1 p.Pro975Ala (c.2923C>G) in the general population?

EHMT1 p.Pro975Ala (c.2923C>G) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about EHMT1 p.Pro975Ala (c.2923C>G)?

AlphaMissense predicts ambiguous (score 0.5344) — an in-silico prediction, not a clinical call.

EHMT1 p.Pro975Ala

c.2923C>G · rs2538651378 · VCV2701255

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5344 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

Kleefstra syndrome 1

Computational evidence

Protein change
AlphaMissense	0.5344	ambiguous
REVEL	0.354	indeterminate
SaProt	LLR -7.03	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 356 bp · p 0.28 · regional, not allelic
Overall
CADD	24.2	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 0.000593% European (non-Finnish) · 7/1,180,036 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,461,616 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.Pro975Ala
Coding: c.2923C>G
MANE Select: NM_024757
dbSNP: rs2538651378
Type: single nucleotide variant
Location: chr9:137813061 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.89 · 22 PDB
Residue 975: an α-helix

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.Pro975= 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
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-pro975ala (accessed [today's date]).

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