Is KMT2D p.Pro99Ser (c.295C>T) pathogenic?

KMT2D p.Pro99Ser (c.295C>T) is classified Uncertain significance in KMT2D (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-23). AlphaMissense: likely benign (0.0671); Very rare (popmax 0.00223%, eas); Associated with choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome.

How common is KMT2D p.Pro99Ser (c.295C>T) in the general population?

KMT2D p.Pro99Ser (c.295C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about KMT2D p.Pro99Ser (c.295C>T)?

AlphaMissense predicts likely benign (score 0.0671) — an in-silico prediction, not a clinical call.

KMT2D p.Pro99Ser

Q: What condition is associated with KMT2D p.Pro99Ser (c.295C>T)?

KMT2D p.Pro99Ser (c.295C>T) is associated with choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome, Kabuki syndrome 1 (ClinVar).

c.295C>T · rs886049487 · VCV3891506

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0671 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome

Computational evidence

Protein change
AlphaMissense	0.0671	likely benign
REVEL	0.27	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -0.18, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 779 bp · p 0.092 · regional, not allelic
Overall
CADD	18.23	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,852 alleles

Overall 6.2e-05% 1/1,613,234 alleles · very rare exomes 1/1,461,014 · genomes 0/152,220 · joint denominator

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.Pro99Ser
Coding: c.295C>T
MANE Select: NM_003482
dbSNP: rs886049487
Type: single nucleotide variant
Location: chr12:49054633 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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

Disease context

choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Kabuki syndrome 1

Similar variants

KMT2D p.Pro99fs Likely pathogenic same residue
KMT2D c.10740+1G>A Pathogenic ★★ same condition
KMT2D c.14075+1G>A Pathogenic/Likely pathogenic ★★ same condition
KMT2D c.14251+1G>C Likely pathogenic ★★ same condition
KMT2D c.16338+1G>T Pathogenic/Likely pathogenic ★★ same condition
KMT2D c.16338+2T>C Pathogenic/Likely pathogenic ★★ same condition
KMT2D c.177-2A>G Pathogenic/Likely pathogenic ★★ same condition
KMT2D p.Ala3541Pro 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-pro99ser (accessed [today's date]).

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