Is KAT2B p.Pro406Ser (c.1216C>T) pathogenic?

KAT2B p.Pro406Ser (c.1216C>T) is classified Likely benign in KAT2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-27). AlphaMissense: likely benign (0.069); Very rare (popmax 0.005%, amr).

How common is KAT2B p.Pro406Ser (c.1216C>T) in the general population?

KAT2B p.Pro406Ser (c.1216C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about KAT2B p.Pro406Ser (c.1216C>T)?

AlphaMissense predicts likely benign (score 0.069) — an in-silico prediction, not a clinical call.

KAT2B p.Pro406Ser

c.1216C>T · VCV4089779

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.069 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.069	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -5.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.86	GERP 0.29, phastCons 0.27
Regional constraint	o/e 0.84	unconstrained · MANE · 13 kb · p 0.0084 · regional, not allelic
Overall
CADD	12.79	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,978 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00031% 5/1,613,964 alleles · very rare exomes 4/1,461,790 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,993
Remaining individualsnot grpmax-eligible	0.0032%	31,239

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: KAT2B
Protein: p.Pro406Ser
Coding: c.1216C>T
MANE Select: NM_003884
Type: single nucleotide variant
Location: chr3:20119663 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.22 · 25 PDB
Residue 406: the 'disordered' region

Full KAT2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KAT2B p.Ile198Val Uncertain significance ★★ ⚠ same type
KAT2B c.1043+115G>A Benign ★★ same type
KAT2B c.1044-72T>C Benign ★★ same type
KAT2B c.1151-47G>T Benign ★★ same type
KAT2B c.1623-40C>G Benign ★★ same type
KAT2B c.1861-37T>C Benign ★★ same type
KAT2B c.1861-98G>T Benign ★★ same type
KAT2B c.2004+48C>T Benign ★★ 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/kat2b-p-pro406ser (accessed [today's date]).

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