Is KMT2C p.Pro4416Ser (c.13246C>T) pathogenic?

KMT2C p.Pro4416Ser (c.13246C>T) is classified Benign in KMT2C (ClinVar, Single submitter, 2 submitters; last evaluated 2023-03-27). AlphaMissense: ambiguous (0.3464); Rare (popmax 0.238%, eas).

How common is KMT2C p.Pro4416Ser (c.13246C>T) in the general population?

KMT2C p.Pro4416Ser (c.13246C>T) is rare (popmax 0.238%, eas) (gnomAD).

What do computational predictors say about KMT2C p.Pro4416Ser (c.13246C>T)?

AlphaMissense predicts ambiguous (score 0.3464) — an in-silico prediction, not a clinical call.

KMT2C p.Pro4416Ser

c.13246C>T · rs201443050 · VCV134814

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3464 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.238%, eas)

Computational evidence

Protein change
AlphaMissense	0.3464	ambiguous
REVEL	0.566	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 4, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 250 bp · p 4.7e-10 · regional, not allelic
Overall
CADD	22.5	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 0.238% East Asian · 107/44,872 alleles

Filtering AF 0.202% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.188%

Overall 0.00688% 111/1,614,118 alleles · rare exomes 88/1,461,856 · genomes 23/152,262 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.238%	419
Remaining individualsnot grpmax-eligible	0.0064%	15,628

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.Pro4416Ser
Coding: c.13246C>T
MANE Select: NM_170606
dbSNP: rs201443050
Type: single nucleotide variant
Location: chr7:152148681 (GRCh38)
Gene constraint: LOEUF 0.202 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 4416: a UniProt-annotated variant site (in klefs2)

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

Similar variants

KMT2C c.1013-1G>A Pathogenic/Likely pathogenic ★★ same type
KMT2C c.14344-1G>A Pathogenic/Likely pathogenic ★★ same type
KMT2C p.Arg1481Ter Pathogenic/Likely pathogenic ★★ same type
KMT2C p.Arg1906Ter Pathogenic ★★ same type
KMT2C p.Arg2066Ter Pathogenic ★★ same type
KMT2C p.Arg2609Ter Pathogenic/Likely pathogenic ★★ same type
KMT2C p.Arg2610Ter Pathogenic/Likely pathogenic ★★ same type
KMT2C p.Arg3079Ter 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/kmt2c-p-pro4416ser (accessed [today's date]).

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