Is KMT2A p.Pro45= (c.135G>A) pathogenic?

KMT2A p.Pro45= (c.135G>A) is classified Benign/Likely benign in KMT2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-31). Rare (popmax 0.456%, sas); Associated with Wiedemann-Steiner syndrome.

What condition is associated with KMT2A p.Pro45= (c.135G>A)?

KMT2A p.Pro45= (c.135G>A) is associated with Wiedemann-Steiner syndrome (ClinVar).

How common is KMT2A p.Pro45= (c.135G>A) in the general population?

KMT2A p.Pro45= (c.135G>A) is rare (popmax 0.456%, sas) (gnomAD).

KMT2A p.Pro45=

c.135G>A · rs9332746 · VCV1566281

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.456%, sas)

Conditions

Wiedemann-Steiner syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.65, phastCons 1
Overall
CADD	13.57	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.456% South Asian · 103/22,588 alleles

Filtering AF 0.385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.358%

Overall 0.012% 134/1,115,862 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.456%	219
Remaining individualsnot grpmax-eligible	0.0416%	2,403
Middle Eastern	0.0362%	2,762
European (non-Finnish)	0.00155%	64,596

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: KMT2A
Protein: p.Pro45=
Coding: c.135G>A
MANE Select: NM_001197104
dbSNP: rs9332746
Type: single nucleotide variant
Location: chr11:118436647 (GRCh38)
Gene constraint: LOEUF 0.065 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 45: the 'disordered' region

Full KMT2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Wiedemann-Steiner syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KMT2A p.Pro45Ser Uncertain significance ★ ⚠ same residue
KMT2A p.Pro45fs Likely pathogenic ★ same residue
KMT2A p.Pro45Arg Uncertain significance ★★ ⚠ same residue
KMT2A p.Pro45Thr Uncertain significance ★ ⚠ same residue
KMT2A c.11071+1G>A Pathogenic ★★ same condition
KMT2A c.4012+1G>C Pathogenic ★★ same condition
KMT2A c.502+1G>A Pathogenic ★★ same condition
KMT2A c.6079+2T>C 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/kmt2a-p-pro45 (accessed [today's date]).

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