Is KMT2C p.Pro22Ser (c.64C>T) pathogenic?

KMT2C p.Pro22Ser (c.64C>T) is classified Uncertain significance in KMT2C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.2034); Ultra-rare (popmax 0.0128%, afr); Associated with Inborn genetic diseases.

What condition is associated with KMT2C p.Pro22Ser (c.64C>T)?

KMT2C p.Pro22Ser (c.64C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KMT2C p.Pro22Ser (c.64C>T) in the general population?

KMT2C p.Pro22Ser (c.64C>T) is ultra-rare (popmax 0.0128%, afr) (gnomAD).

What do computational predictors say about KMT2C p.Pro22Ser (c.64C>T)?

AlphaMissense predicts likely benign (score 0.2034) — an in-silico prediction, not a clinical call.

KMT2C p.Pro22Ser

c.64C>T · VCV4623081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2034 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0128%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2034	likely benign
REVEL	0.429	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP -0.59, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 90 bp · p 0.26 · regional, not allelic
Overall
CADD	18.81	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 0.0128% African / African-American · 9/70,498 alleles

Filtering AF 0.00659% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00493%

Overall 0.000587% 9/1,532,710 alleles · ultra-rare

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.Pro22Ser
Coding: c.64C>T
MANE Select: NM_170606
Type: single nucleotide variant
Location: chr7:152435723 (GRCh38)
Gene constraint: LOEUF 0.202 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 22: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KMT2C p.Ala286Thr Uncertain significance ★★ ⚠ same condition
KMT2C p.Ala3750Ser Uncertain significance ★★ ⚠ same condition
KMT2C p.Arg1229Gly Uncertain significance ★★ ⚠ same condition
KMT2C p.Arg4828His Uncertain significance ★★ ⚠ same condition
KMT2C p.Arg886Cys Uncertain significance ★★ ⚠ same condition
KMT2C p.Asn4282Ser Uncertain significance ★★ same condition
KMT2C p.Asp2157His Uncertain significance ★★ same condition
KMT2C p.Asp2723Gly Uncertain significance ★★ 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-pro22ser (accessed [today's date]).

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