Is KMT2D p.Ser1237Phe (c.3710C>T) pathogenic?

KMT2D p.Ser1237Phe (c.3710C>T) is classified Conflicting classifications of pathogenicity in KMT2D (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-20). AlphaMissense: likely pathogenic (0.6882); Very rare (popmax 0.00267%, afr); Associated with Kabuki syndrome.

What condition is associated with KMT2D p.Ser1237Phe (c.3710C>T)?

KMT2D p.Ser1237Phe (c.3710C>T) is associated with Kabuki syndrome (ClinVar).

How common is KMT2D p.Ser1237Phe (c.3710C>T) in the general population?

KMT2D p.Ser1237Phe (c.3710C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about KMT2D p.Ser1237Phe (c.3710C>T)?

AlphaMissense predicts likely pathogenic (score 0.6882) — an in-silico prediction, not a clinical call.

KMT2D p.Ser1237Phe

c.3710C>T · rs374437749 · VCV2635863

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6882 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Kabuki syndrome

Computational evidence

Protein change
AlphaMissense	0.6882	likely pathogenic
REVEL	0.368	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,944 bp · p 0.018 · regional, not allelic
Overall
CADD	24.1	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 · 2/74,936 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.0018% 29/1,613,774 alleles · very rare exomes 27/1,461,562 · genomes 2/152,212 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,821
African / African-Americangrpmax	0.00267%	37,468
European (non-Finnish)	0.00195%	51,299
South Asian	0.0011%	91,086

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser1237Phe
Coding: c.3710C>T
MANE Select: NM_003482
dbSNP: rs374437749
Type: single nucleotide variant
Location: chr12:49049878 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1237: 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

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

Similar variants

KMT2D p.Ser1237= Likely benign ★ same residue
KMT2D p.Ser1237Ala Likely benign ★ 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-ser1237phe (accessed [today's date]).

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