Is KMT2D p.Pro646= (c.1938C>G) pathogenic?

KMT2D p.Pro646= (c.1938C>G) is classified Benign/Likely benign in KMT2D (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-11). Low-frequency (popmax 3.11%, eas); Associated with Kabuki syndrome.

What condition is associated with KMT2D p.Pro646= (c.1938C>G)?

KMT2D p.Pro646= (c.1938C>G) is associated with Kabuki syndrome, Kabuki syndrome 1 (ClinVar).

How common is KMT2D p.Pro646= (c.1938C>G) in the general population?

KMT2D p.Pro646= (c.1938C>G) is low-frequency (popmax 3.11%, eas) (gnomAD).

KMT2D p.Pro646=

c.1938C>G · rs147212187 · VCV158747

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.11%, eas)

Conditions

Kabuki syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6	GERP -3
Overall
CADD	1.065	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.11% East Asian · 1,344/43,254 alleles

Filtering AF 2.97% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.91%

Overall 0.0996% 1,544/1,549,424 alleles · low-frequency exomes 1,410/1,413,366 · genomes 134/136,058 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	3.11%	32
Remaining individualsnot grpmax-eligible	0.173%	578
South Asian	0.0313%	3,195
African / African-American	0.0233%	4,283
Middle Eastern	0.0171%	5,850
Admixed American	0.00694%	14,414
European (non-Finnish)	0.00415%	24,118

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.Pro646=
Coding: c.1938C>G
MANE Select: NM_003482
dbSNP: rs147212187
Type: single nucleotide variant
Location: chr12:49051745 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 646: a UniProt-annotated variant site (in kabuk1); the 'disordered' region; the '15 x 5 aa repeats of s/p-p-p-e/p-e/a' 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

Also linked: Kabuki syndrome 1

Similar variants

KMT2D c.10740+1G>A Pathogenic ★★ same condition
KMT2D c.14075+1G>A Pathogenic/Likely pathogenic ★★ same condition
KMT2D c.14251+1G>C Likely pathogenic ★★ same condition
KMT2D c.16338+1G>T Pathogenic/Likely pathogenic ★★ same condition
KMT2D c.16338+2T>C Pathogenic/Likely pathogenic ★★ same condition
KMT2D c.177-2A>G Pathogenic/Likely pathogenic ★★ same condition
KMT2D c.4132-2A>G Pathogenic ★★ same condition
KMT2D c.5189-2A>G 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/kmt2d-p-pro646 (accessed [today's date]).

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