Is KAT2B p.Pro121Arg (c.362C>G) pathogenic?

KAT2B p.Pro121Arg (c.362C>G) is classified Uncertain significance in KAT2B (ClinVar, Single submitter, 2 submitters; last evaluated 2023-08-02). AlphaMissense: ambiguous (0.4549); Ultra-rare (popmax 0.0203%, nfe).

How common is KAT2B p.Pro121Arg (c.362C>G) in the general population?

KAT2B p.Pro121Arg (c.362C>G) is ultra-rare (popmax 0.0203%, nfe) (gnomAD).

What do computational predictors say about KAT2B p.Pro121Arg (c.362C>G)?

AlphaMissense predicts ambiguous (score 0.4549) — an in-silico prediction, not a clinical call.

KAT2B p.Pro121Arg

c.362C>G · rs200560854 · VCV2590339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4549 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4549	ambiguous
REVEL	0.17	moderately benign-leaning
SaProt	LLR -7.70	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 32 kb · p 0.32 · regional, not allelic
Overall
CADD	26.0	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 0.0203% European (non-Finnish) · 239/1,179,372 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0173%

Overall 0.0161% 260/1,613,264 alleles · ultra-rare exomes 244/1,461,116 · genomes 16/152,148 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0203%	4,935
Admixed American	0.0117%	8,569
Remaining individualsnot grpmax-eligible	0.0112%	8,923
African / African-American	0.00668%	14,973
South Asian	0.0022%	45,532

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.Pro121Arg
Coding: c.362C>G
MANE Select: NM_003884
dbSNP: rs200560854
Type: single nucleotide variant
Location: chr3:20072391 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.22 · 25 PDB

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

Similar variants

KAT2B p.Pro121= Likely benign same residue
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

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-pro121arg (accessed [today's date]).

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