Is EHMT2 p.Ser451Arg (c.1351A>C) pathogenic?

EHMT2 p.Ser451Arg (c.1351A>C) is classified Uncertain significance in EHMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-12). AlphaMissense: likely pathogenic (0.9947); Very rare (popmax 0.000254%, nfe).

How common is EHMT2 p.Ser451Arg (c.1351A>C) in the general population?

EHMT2 p.Ser451Arg (c.1351A>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about EHMT2 p.Ser451Arg (c.1351A>C)?

AlphaMissense predicts likely pathogenic (score 0.9947) — an in-silico prediction, not a clinical call.

EHMT2 p.Ser451Arg

c.1351A>C · VCV3844016

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9947	likely pathogenic
REVEL	0.497	indeterminate
SaProt	LLR -10.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 2.6, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 5,669 bp · p 7.9e-23 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,960 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,084 alleles · very rare exomes 3/1,460,888 · genomes 0/152,196 · joint denominator

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: EHMT2
Protein: p.Ser451Arg
Coding: c.1351A>C
MANE Select: NM_006709
Type: single nucleotide variant
Location: chr6:31888613 (GRCh38)
Gene constraint: LOEUF 0.492 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 69.25 · 34 PDB
Residue 451: a β-strand

Full EHMT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EHMT2 p.Ala1077Thr Pathogenic ★★ same type
EHMT2 p.Ala1077Ser Pathogenic ★ same type
EHMT2 p.Asn1112Ser Pathogenic ★ ⚠ same type
EHMT2 p.Lys1162Arg Pathogenic ★ same type
EHMT2 p.Phe1158Leu Pathogenic ★ same type
EHMT2 c.328+2T>G Uncertain significance ★ same type
EHMT2 p.Ala137Ser Uncertain significance ★ ⚠ same type
EHMT2 p.Ala17Pro Uncertain significance ★ ⚠ same type

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/ehmt2-p-ser451arg (accessed [today's date]).

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