Is KMT2C p.Arg2139Ter (c.6415C>T) pathogenic?

KMT2C p.Arg2139Ter (c.6415C>T) is classified Likely pathogenic in KMT2C (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.000169%, nfe); Associated with KMT2C-related NDD.

What condition is associated with KMT2C p.Arg2139Ter (c.6415C>T)?

KMT2C p.Arg2139Ter (c.6415C>T) is associated with KMT2C-related NDD (ClinVar).

How common is KMT2C p.Arg2139Ter (c.6415C>T) in the general population?

KMT2C p.Arg2139Ter (c.6415C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

KMT2C p.Arg2139Ter

c.6415C>T · VCV3236536

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

KMT2C-related NDD

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 36 of 59
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -2.6, phastCons 0.99
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,994 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,052 alleles · very rare exomes 2/1,461,870 · genomes 0/152,182 · joint denominator

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: KMT2C
Protein: p.Arg2139Ter
Coding: c.6415C>T
MANE Select: NM_170606
Type: single nucleotide variant
Location: chr7:152181445 (GRCh38)
Gene constraint: LOEUF 0.202 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2139: a UniProt-annotated variant site (in klefs2); the 'disordered' region

Full KMT2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

KMT2C-related NDD

Similar variants

KMT2C p.Arg2139Gln Uncertain significance ★ ⚠ same residue
KMT2C p.Arg2139= Likely benign ★ same residue
KMT2C c.1013-1G>A Pathogenic/Likely pathogenic ★★ same condition
KMT2C c.14344-1G>A Pathogenic/Likely pathogenic ★★ same condition
KMT2C p.Arg2066Ter Pathogenic ★★ same condition
KMT2C p.Arg2610Ter Pathogenic/Likely pathogenic ★★ same condition
KMT2C p.Arg3995Ter Pathogenic/Likely pathogenic ★★ same condition
KMT2C p.Lys564Ter 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/kmt2c-p-arg2139ter (accessed [today's date]).

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