Is KMT2D p.Pro655= (c.1965C>A) pathogenic?

KMT2D p.Pro655= (c.1965C>A) is classified Benign/Likely benign in KMT2D (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-01). Rare (popmax 0.208%, mid); Associated with Kabuki syndrome.

What condition is associated with KMT2D p.Pro655= (c.1965C>A)?

KMT2D p.Pro655= (c.1965C>A) is associated with Kabuki syndrome (ClinVar).

How common is KMT2D p.Pro655= (c.1965C>A) in the general population?

KMT2D p.Pro655= (c.1965C>A) is rare (popmax 0.208%, mid) (gnomAD).

KMT2D p.Pro655=

c.1965C>A · rs200939188 · VCV309084

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.208%, mid)

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 -2	GERP -2.6
Overall
CADD	1.786	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.208% Middle Eastern · 12/5,764 alleles

Filtering AF 0.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0942%

Overall 0.0723% 1,118/1,545,494 alleles · rare exomes 1,040/1,402,534 · genomes 78/142,960 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.208%	480
Amishnot grpmax-eligible	0.117%	858
Remaining individualsnot grpmax-eligible	0.085%	1,176
European (non-Finnish)	0.085%	1,176
Admixed American	0.0785%	1,274
Ashkenazi Jewishnot grpmax-eligible	0.0712%	1,404
Finnishnot grpmax-eligible	0.0149%	6,731
African / African-American	0.0114%	8,785
South Asian	0.00909%	10,997

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.Pro655=
Coding: c.1965C>A
MANE Select: NM_003482
dbSNP: rs200939188
Type: single nucleotide variant
Location: chr12:49051718 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 655: 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

Similar variants

KMT2D p.Pro655Ala Uncertain significance ★ ⚠ same residue
KMT2D p.Pro655Leu Uncertain significance ★ ⚠ same residue
KMT2D p.Pro655Ser Uncertain significance ★ ⚠ same residue
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

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-pro655 (accessed [today's date]).

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