Is KMT2D p.Val231= (c.693G>A) pathogenic?

KMT2D p.Val231= (c.693G>A) is classified Likely benign in KMT2D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-17). Very rare (popmax 0.00461%, nfe); Associated with Kabuki syndrome.

What condition is associated with KMT2D p.Val231= (c.693G>A)?

KMT2D p.Val231= (c.693G>A) is associated with Kabuki syndrome (ClinVar).

How common is KMT2D p.Val231= (c.693G>A) in the general population?

KMT2D p.Val231= (c.693G>A) is very rare (popmax 0.00461%, nfe) (gnomAD).

KMT2D p.Val231=

c.693G>A · rs1442209147 · VCV3048861

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00461%, nfe)

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 -5.4	GERP -4.4
Overall
CADD	1.507	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00461% European (non-Finnish) · 54/1,171,708 alleles

Filtering AF 0.00361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00323%

Overall 0.00363% 58/1,595,820 alleles · very rare exomes 56/1,443,598 · genomes 2/152,222 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00485%	20,623
European (non-Finnish)grpmax	0.00461%	21,698
African / African-American	0.00134%	74,438

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val231=
Coding: c.693G>A
MANE Select: NM_003482
dbSNP: rs1442209147
Type: single nucleotide variant
Location: chr12:49053622 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 231: a UniProt-annotated variant site (in kabuk1); a turn

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.Val231Ala Benign/Likely benign ★★ same residue
KMT2D p.Val231Met 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
KMT2D p.Arg1615Ter 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-val231 (accessed [today's date]).

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