Is KMT2B p.Met2326Val (c.6976A>G) pathogenic?

KMT2B p.Met2326Val (c.6976A>G) is classified Uncertain significance in KMT2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.2645); Very rare (popmax 0.00135%, afr).

How common is KMT2B p.Met2326Val (c.6976A>G) in the general population?

KMT2B p.Met2326Val (c.6976A>G) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about KMT2B p.Met2326Val (c.6976A>G)?

AlphaMissense predicts likely benign (score 0.2645) — an in-silico prediction, not a clinical call.

KMT2B p.Met2326Val

c.6976A>G · rs1039247530 · VCV2579594

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2645 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Computational evidence

Protein change
AlphaMissense	0.2645	likely benign
REVEL	0.472	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	Δ0.22	acceptor loss · deltas
Pangolin	Δ0.33	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 5,903 bp · p 0.013 · regional, not allelic
Overall
CADD	22.3	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 0.00135% African / African-American · 1/74,246 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000315% 5/1,585,746 alleles · very rare exomes 4/1,433,806 · genomes 1/151,940 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,246
European (non-Finnish)	0.000343%	291,588

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: KMT2B
Protein: p.Met2326Val
Coding: c.6976A>G
MANE Select: NM_014727
dbSNP: rs1039247530
Type: single nucleotide variant
Location: chr19:35733613 (GRCh38)
Gene constraint: LOEUF 0.127 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2326: a UniProt-annotated variant site (in dyt28); a UniProt-annotated variant site (in mrd68); the 'disordered' region

Full KMT2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KMT2B p.Met2326Arg Uncertain significance ★ ⚠ same residue
KMT2B p.Ala1616Val Likely pathogenic ★★ same type
KMT2B p.Ala2641Thr Likely pathogenic ★★ same type
KMT2B p.Arg142Ter Pathogenic ★★ same type
KMT2B p.Arg1597Trp Pathogenic/Likely pathogenic ★★ same type
KMT2B p.Arg1705Ter Pathogenic ★★ same type
KMT2B p.Arg2565Gly Likely pathogenic ★★ same type
KMT2B p.Arg2610Cys 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/kmt2b-p-met2326val (accessed [today's date]).

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