Is KMT2D p.Pro271Ser (c.811C>T) pathogenic?

KMT2D p.Pro271Ser (c.811C>T) is classified Uncertain significance in KMT2D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-12). AlphaMissense: likely pathogenic (0.8007); Very rare (popmax 8.49e-05%, nfe); Associated with choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome.

How common is KMT2D p.Pro271Ser (c.811C>T) in the general population?

KMT2D p.Pro271Ser (c.811C>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about KMT2D p.Pro271Ser (c.811C>T)?

AlphaMissense predicts likely pathogenic (score 0.8007) — an in-silico prediction, not a clinical call.

KMT2D p.Pro271Ser

Q: What condition is associated with KMT2D p.Pro271Ser (c.811C>T)?

KMT2D p.Pro271Ser (c.811C>T) is associated with choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome, Kabuki syndrome 1 (ClinVar).

c.811C>T · VCV3574876

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8007 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.8007	likely pathogenic
REVEL	0.592	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 1,303 bp · p 1.2e-05 · regional, not allelic
Overall
CADD	24.4	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 8.49e-05% European (non-Finnish) · 1/1,177,680 alleles

Overall 6.21e-05% 1/1,609,234 alleles · very rare exomes 1/1,456,996 · genomes 0/152,238 · 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.Pro271Ser
Coding: c.811C>T
MANE Select: NM_003482
Type: single nucleotide variant
Location: chr12:49053504 (GRCh38)
Gene constraint: LOEUF 0.141 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 271: a UniProt-annotated variant site (in kabuk1)

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.Pro271Arg Likely benign ★★ 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-pro271ser (accessed [today's date]).

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