Is KMT2D p.Pro1108Ser (c.3322C>T) pathogenic?

KMT2D p.Pro1108Ser (c.3322C>T) is classified Uncertain significance in KMT2D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-20). AlphaMissense: likely benign (0.1775); Very rare (popmax 0.00267%, afr); Associated with KMT2D-related disorder.

What condition is associated with KMT2D p.Pro1108Ser (c.3322C>T)?

KMT2D p.Pro1108Ser (c.3322C>T) is associated with KMT2D-related disorder (ClinVar).

How common is KMT2D p.Pro1108Ser (c.3322C>T) in the general population?

KMT2D p.Pro1108Ser (c.3322C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about KMT2D p.Pro1108Ser (c.3322C>T)?

AlphaMissense predicts likely benign (score 0.1775) — an in-silico prediction, not a clinical call.

KMT2D p.Pro1108Ser

c.3322C>T · rs758024031 · VCV2629546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1775 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

KMT2D-related disorder

Computational evidence

Protein change
AlphaMissense	0.1775	likely benign
REVEL	0.384	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,944 bp · p 0.018 · regional, not allelic
Overall
CADD	22.6	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 0.00267% African / African-American · 2/74,896 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,611,948 alleles · very rare exomes 2/1,459,744 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,448
European (non-Finnish)	8.48e-05%	1,179,066

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.Pro1108Ser
Coding: c.3322C>T
MANE Select: NM_003482
dbSNP: rs758024031
Type: single nucleotide variant
Location: chr12:49050266 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1108: a UniProt-annotated variant site (in kabuk1); the 'disordered' region

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

Disease context

KMT2D-related disorder

Similar variants

KMT2D p.Arg2099Ter Pathogenic ★★ same condition
KMT2D p.Arg2410Ter Pathogenic ★★ same condition
KMT2D p.Arg2685Ter Pathogenic/Likely pathogenic ★★ same condition
KMT2D p.Arg3321Ter Pathogenic ★★ same condition
KMT2D p.Arg3982Ter Pathogenic ★★ same condition
KMT2D p.Arg4282Ter Pathogenic ★★ same condition
KMT2D p.Arg5027Ter Pathogenic ★★ same condition
KMT2D p.Arg5154Gln 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/kmt2d-p-pro1108ser (accessed [today's date]).

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