Is KAT2B p.Arg653Trp (c.1957C>T) pathogenic?

KAT2B p.Arg653Trp (c.1957C>T) is classified Benign in KAT2B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-21). AlphaMissense: likely benign (0.2385); Low-frequency (popmax 1.05%, mid); Associated with KAT2B-related disorder.

What condition is associated with KAT2B p.Arg653Trp (c.1957C>T)?

KAT2B p.Arg653Trp (c.1957C>T) is associated with KAT2B-related disorder (ClinVar).

How common is KAT2B p.Arg653Trp (c.1957C>T) in the general population?

KAT2B p.Arg653Trp (c.1957C>T) is low-frequency (popmax 1.05%, mid) (gnomAD).

What do computational predictors say about KAT2B p.Arg653Trp (c.1957C>T)?

AlphaMissense predicts likely benign (score 0.2385) — an in-silico prediction, not a clinical call.

KAT2B p.Arg653Trp

c.1957C>T · rs116196143 · VCV3037788

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2385 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.05%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

KAT2B-related disorder

Computational evidence

Protein change
AlphaMissense	0.2385	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -14.40	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.1, phastCons 0.86
Regional constraint	o/e 0.77	unconstrained · MANE · 16 kb · p 0.00012 · regional, not allelic
Overall
CADD	24.3	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 1.05% Middle Eastern · 63/5,998 alleles

Filtering AF 0.842% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.767%

Overall 0.325% 5,246/1,613,712 alleles · low-frequency exomes 4,897/1,461,444 · genomes 349/152,268 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.81%	55
Middle Easterngrpmax	1.05%	95
Remaining individualsnot grpmax-eligible	0.438%	228
South Asian	0.378%	265
European (non-Finnish)	0.326%	307
Admixed American	0.163%	612
Finnishnot grpmax-eligible	0.0703%	1,423
African / African-American	0.0493%	2,028
East Asian	0.00669%	14,957

Ashkenazi Jewish 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: KAT2B
Protein: p.Arg653Trp
Coding: c.1957C>T
MANE Select: NM_003884
dbSNP: rs116196143
Type: single nucleotide variant
Location: chr3:20140317 (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

Disease context

KAT2B-related disorder

Similar variants

KAT2B p.Ile764Val Uncertain significance ★ ⚠ same condition
KAT2B p.Ala466Val Uncertain significance ⚠ same condition
KAT2B p.Gly208Ala Uncertain significance ⚠ same condition
KAT2B p.Ser434Cys Uncertain significance ⚠ same condition
KAT2B c.2157-5T>C Likely benign same condition
KAT2B c.670-3A>C Likely benign same condition
KAT2B c.852-5C>T Likely benign same condition
KAT2B p.Ala144= Likely benign 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/kat2b-p-arg653trp (accessed [today's date]).

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