Is KAT2A p.Pro215Ser (c.643C>T) pathogenic?

KAT2A p.Pro215Ser (c.643C>T) is classified Uncertain significance in KAT2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: likely pathogenic (0.9891); Very rare (popmax 0.000169%, nfe).

How common is KAT2A p.Pro215Ser (c.643C>T) in the general population?

KAT2A p.Pro215Ser (c.643C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about KAT2A p.Pro215Ser (c.643C>T)?

AlphaMissense predicts likely pathogenic (score 0.9891) — an in-silico prediction, not a clinical call.

KAT2A p.Pro215Ser

c.643C>T · rs1555666970 · VCV2487831

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9891	likely pathogenic
REVEL	0.299	indeterminate
SaProt	LLR -11.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 1,776 bp · p 9e-13 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,006 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,156 alleles · very rare exomes 2/1,461,858 · genomes 0/152,298 · 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: KAT2A
Protein: p.Pro215Ser
Coding: c.643C>T
MANE Select: NM_021078
dbSNP: rs1555666970
Type: single nucleotide variant
Location: chr17:42120086 (GRCh38)
Gene constraint: LOEUF 0.587 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.62 · 15 PDB

Full KAT2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KAT2A c.464-18C>G Benign ★★ same type
KAT2A p.Leu664= Benign ★★ same type
KAT2A p.Leu719= Benign ★★ same type
KAT2A p.Ala274Val Uncertain significance ★ ⚠ same type
KAT2A p.Ala426Val Uncertain significance ★ ⚠ same type
KAT2A p.Ala53Ser Uncertain significance ★ ⚠ same type
KAT2A p.Ala53Val Uncertain significance ★ ⚠ same type
KAT2A p.Arg171Gly Uncertain significance ★ ⚠ 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/kat2a-p-pro215ser (accessed [today's date]).

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