Is KMT2C p.Glu4792Asp (c.14376G>C) pathogenic?

KMT2C p.Glu4792Asp (c.14376G>C) is classified Uncertain significance in KMT2C (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-25). AlphaMissense: ambiguous (0.5511); Very rare (popmax 0.000932%, nfe); Associated with Kleefstra syndrome 2.

What condition is associated with KMT2C p.Glu4792Asp (c.14376G>C)?

KMT2C p.Glu4792Asp (c.14376G>C) is associated with Kleefstra syndrome 2 (ClinVar).

How common is KMT2C p.Glu4792Asp (c.14376G>C) in the general population?

KMT2C p.Glu4792Asp (c.14376G>C) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about KMT2C p.Glu4792Asp (c.14376G>C)?

AlphaMissense predicts ambiguous (score 0.5511) — an in-silico prediction, not a clinical call.

KMT2C p.Glu4792Asp

c.14376G>C · rs1169599565 · VCV1709318

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5511 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Conditions

Kleefstra syndrome 2

Computational evidence

Protein change
AlphaMissense	0.5511	ambiguous
REVEL	0.505	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP 1.4, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 8,356 bp · p 5e-15 · regional, not allelic
Overall
CADD	22.4	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 0.000932% European (non-Finnish) · 11/1,179,986 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,614,008 alleles · very rare exomes 11/1,461,846 · genomes 0/152,162 · 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.Glu4792Asp
Coding: c.14376G>C
MANE Select: NM_170606
dbSNP: rs1169599565
Type: single nucleotide variant
Location: chr7:152139759 (GRCh38)
Gene constraint: LOEUF 0.202 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 4792: a UniProt-annotated variant site (in klefs2); the set domain

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

Disease context

Kleefstra syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KMT2C p.Arg1481Ter Pathogenic/Likely pathogenic ★★ same condition
KMT2C p.Arg1906Ter Pathogenic ★★ same condition
KMT2C p.Arg2609Ter Pathogenic/Likely pathogenic ★★ same condition
KMT2C p.Arg3079Ter Pathogenic ★★ same condition
KMT2C p.Arg3995Ter Pathogenic/Likely pathogenic ★★ same condition
KMT2C p.Arg4533Ter Pathogenic/Likely pathogenic ★★ same condition
KMT2C p.Arg4690Ter 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-glu4792asp (accessed [today's date]).

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