Is KMT2D p.Ala2139Val (c.6416C>T) pathogenic?

KMT2D p.Ala2139Val (c.6416C>T) is classified Likely benign in KMT2D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1377); Very rare (popmax 0.00716%, amr); Associated with Inborn genetic diseases.

What condition is associated with KMT2D p.Ala2139Val (c.6416C>T)?

KMT2D p.Ala2139Val (c.6416C>T) is associated with Inborn genetic diseases, Kabuki syndrome (ClinVar).

How common is KMT2D p.Ala2139Val (c.6416C>T) in the general population?

KMT2D p.Ala2139Val (c.6416C>T) is very rare (popmax 0.00716%, amr) (gnomAD).

What do computational predictors say about KMT2D p.Ala2139Val (c.6416C>T)?

AlphaMissense predicts likely benign (score 0.1377) — an in-silico prediction, not a clinical call.

KMT2D p.Ala2139Val

c.6416C>T · rs754730634 · VCV1565722

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1377 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00716%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1377	likely benign
REVEL	0.414	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 1,442 bp · p 0.014 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00716% Admixed American · 4/55,872 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00534%

Overall 0.00603% 95/1,574,282 alleles · very rare exomes 88/1,422,234 · genomes 7/152,048 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00716%	13,968
European (non-Finnish)	0.00707%	14,151
South Asian	0.00591%	16,919
African / African-American	0.00404%	24,748
East Asian	0.00225%	44,364

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.Ala2139Val
Coding: c.6416C>T
MANE Select: NM_003482
dbSNP: rs754730634
Type: single nucleotide variant
Location: chr12:49041354 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2139: a UniProt-annotated variant site (in kabuk1)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Kabuki syndrome

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.Arg1757Ter Pathogenic ★★ same condition
KMT2D p.Arg1903Ter 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-ala2139val (accessed [today's date]).

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