Is KMT2A p.Pro45Ser (c.133C>T) pathogenic?

KMT2A p.Pro45Ser (c.133C>T) is classified Uncertain significance in KMT2A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-08). AlphaMissense: likely benign (0.073); Very rare (popmax 0.000106%, nfe); Associated with Wiedemann-Steiner syndrome.

What condition is associated with KMT2A p.Pro45Ser (c.133C>T)?

KMT2A p.Pro45Ser (c.133C>T) is associated with Wiedemann-Steiner syndrome (ClinVar).

How common is KMT2A p.Pro45Ser (c.133C>T) in the general population?

KMT2A p.Pro45Ser (c.133C>T) is very rare (popmax 0.000106%, nfe) (gnomAD).

What do computational predictors say about KMT2A p.Pro45Ser (c.133C>T)?

AlphaMissense predicts likely benign (score 0.073) — an in-silico prediction, not a clinical call.

KMT2A p.Pro45Ser

c.133C>T · rs1949186581 · VCV1027819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.073 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000106%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Wiedemann-Steiner syndrome

Computational evidence

Protein change
AlphaMissense	0.073	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.29, phastCons 0.99
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	14.89	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000106% European (non-Finnish) · 1/943,660 alleles

Overall 9.83e-05% 1/1,017,424 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: KMT2A
Protein: p.Pro45Ser
Coding: c.133C>T
MANE Select: NM_001197104
dbSNP: rs1949186581
Type: single nucleotide variant
Location: chr11:118436645 (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.Pro45= Benign/Likely benign ★★ 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-pro45ser (accessed [today's date]).

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