Is KMT2D p.Pro488Arg (c.1463C>G) pathogenic?

KMT2D p.Pro488Arg (c.1463C>G) is classified Likely benign in KMT2D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-31). AlphaMissense: likely benign (0.1117); Very rare (popmax 0.00167%, amr); Associated with Kabuki syndrome.

What condition is associated with KMT2D p.Pro488Arg (c.1463C>G)?

KMT2D p.Pro488Arg (c.1463C>G) is associated with Kabuki syndrome (ClinVar).

How common is KMT2D p.Pro488Arg (c.1463C>G) in the general population?

KMT2D p.Pro488Arg (c.1463C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about KMT2D p.Pro488Arg (c.1463C>G)?

AlphaMissense predicts likely benign (score 0.1117) — an in-silico prediction, not a clinical call.

KMT2D p.Pro488Arg

c.1463C>G · rs763729848 · VCV1377445

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1117 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Kabuki syndrome

Computational evidence

Protein change
AlphaMissense	0.1117	likely benign
REVEL	0.184	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.28	GERP -3.3, phastCons 0.003
Regional constraint	o/e 1.01	unconstrained · MANE · 2,394 bp · p 0.74 · regional, not allelic
Overall
CADD	8.463	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 0.00167% Admixed American · 1/59,958 alleles

Overall 6.2e-05% 1/1,613,110 alleles · very rare exomes 1/1,461,504 · genomes 0/151,606 · 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: KMT2D
Protein: p.Pro488Arg
Coding: c.1463C>G
MANE Select: NM_003482
dbSNP: rs763729848
Type: single nucleotide variant
Location: chr12:49052220 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 488: a UniProt-annotated variant site (in kabuk1); the 'disordered' region; the '15 x 5 aa repeats of s/p-p-p-e/p-e/a' region

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

Disease context

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

Similar variants

KMT2D p.Pro488= Benign/Likely benign ★★ same residue
KMT2D p.Pro488Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-pro488arg (accessed [today's date]).

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