Is KMT2B p.His1663Pro (c.4988A>C) pathogenic?

KMT2B p.His1663Pro (c.4988A>C) is classified Likely pathogenic in KMT2B (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-07). AlphaMissense: likely pathogenic (0.995); Absent from gnomAD v4.1.

How common is KMT2B p.His1663Pro (c.4988A>C) in the general population?

KMT2B p.His1663Pro (c.4988A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KMT2B p.His1663Pro (c.4988A>C)?

AlphaMissense predicts likely pathogenic (score 0.995) — an in-silico prediction, not a clinical call.

KMT2B p.His1663Pro

c.4988A>C · rs1085307751 · VCV426700

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.995	likely pathogenic ✓ concordant with ClinVar · top 10% in KMT2B
REVEL	0.893	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.20	constrained · MANE · 827 bp · p 2.3e-11 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: KMT2B
Protein: p.His1663Pro
Coding: c.4988A>C
MANE Select: NM_014727
dbSNP: rs1085307751
Type: single nucleotide variant
Location: chr19:35730037 (GRCh38)
Gene constraint: LOEUF 0.127 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1663: a UniProt-annotated variant site (in dyt28); a UniProt-annotated variant site (in mrd68)

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

Similar variants

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
KMT2B p.Arg545Ter 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/kmt2b-p-his1663pro (accessed [today's date]).

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