Is KMT2D p.Pro381= (c.1143C>T) pathogenic?

KMT2D p.Pro381= (c.1143C>T) is classified Likely benign in KMT2D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-10). Very rare (popmax 0.0022%, sas); Associated with Kabuki syndrome.

What condition is associated with KMT2D p.Pro381= (c.1143C>T)?

KMT2D p.Pro381= (c.1143C>T) is associated with Kabuki syndrome (ClinVar).

How common is KMT2D p.Pro381= (c.1143C>T) in the general population?

KMT2D p.Pro381= (c.1143C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

KMT2D p.Pro381=

c.1143C>T · rs1938147808 · VCV1577230

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

Kabuki 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 1.6	GERP -0.84, phastCons 0.99
Overall
CADD	8.23	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,084 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000186% 3/1,613,634 alleles · very rare exomes 2/1,461,506 · genomes 1/152,128 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,542
Remaining individualsnot grpmax-eligible	0.0016%	62,446

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: KMT2D
Protein: p.Pro381=
Coding: c.1143C>T
MANE Select: NM_003482
dbSNP: rs1938147808
Type: single nucleotide variant
Location: chr12:49052679 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 381: a UniProt-annotated variant site (in kabuk1); the 'disordered' region

Full KMT2D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

KMT2D c.10740+1G>A Pathogenic ★★ same condition
KMT2D c.14075+1G>A Pathogenic/Likely pathogenic ★★ same condition
KMT2D c.16338+2T>C Pathogenic/Likely pathogenic ★★ same condition
KMT2D c.4132-2A>G Pathogenic ★★ same condition
KMT2D c.5189-2A>G Pathogenic/Likely pathogenic ★★ same condition
KMT2D p.Arg1615Ter Pathogenic ★★ same condition
KMT2D p.Arg1903Ter Pathogenic ★★ same condition
KMT2D p.Arg2099Ter 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/kmt2d-p-pro381 (accessed [today's date]).

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