Is KMT2C p.Arg1237Ter (c.3709C>T) pathogenic?

KMT2C p.Arg1237Ter (c.3709C>T) is classified Pathogenic in KMT2C (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-26). Very rare (popmax 0.00167%, amr).

How common is KMT2C p.Arg1237Ter (c.3709C>T) in the general population?

KMT2C p.Arg1237Ter (c.3709C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

KMT2C p.Arg1237Ter

c.3709C>T · rs938655561 · VCV1300598

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 23 of 59
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 2.9, phastCons 1
Overall
CADD	37.0	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 0.00167% Admixed American · 1/59,996 alleles

Overall 0.000125% 2/1,600,154 alleles · very rare exomes 2/1,447,928 · genomes 0/152,226 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,996
European (non-Finnish)	8.55e-05%	1,169,078

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.Arg1237Ter
Coding: c.3709C>T
MANE Select: NM_170606
dbSNP: rs938655561
Type: single nucleotide variant
Location: chr7:152220526 (GRCh38)
Gene constraint: LOEUF 0.202 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1237: a UniProt-annotated variant site (in klefs2); the 'disordered' region

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

Similar variants

KMT2C p.Arg1237= Likely benign ★★ same residue
KMT2C c.1013-1G>A Pathogenic/Likely pathogenic ★★ same type
KMT2C c.14344-1G>A Pathogenic/Likely pathogenic ★★ same type
KMT2C p.Arg1481Ter Pathogenic/Likely pathogenic ★★ same type
KMT2C p.Arg1906Ter Pathogenic ★★ same type
KMT2C p.Arg2066Ter Pathogenic ★★ same type
KMT2C p.Arg2609Ter Pathogenic/Likely pathogenic ★★ same type
KMT2C p.Arg2610Ter Pathogenic/Likely pathogenic ★★ same type

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-arg1237ter (accessed [today's date]).

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