Is KAT6A p.Pro994Ser (c.2980C>T) pathogenic?

KAT6A p.Pro994Ser (c.2980C>T) is classified Conflicting classifications of pathogenicity in KAT6A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-12-23). AlphaMissense: likely benign (0.1307); Very rare (popmax 0.00167%, amr); Associated with autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome.

How common is KAT6A p.Pro994Ser (c.2980C>T) in the general population?

KAT6A p.Pro994Ser (c.2980C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about KAT6A p.Pro994Ser (c.2980C>T)?

AlphaMissense predicts likely benign (score 0.1307) — an in-silico prediction, not a clinical call.

KAT6A p.Pro994Ser

Q: What condition is associated with KAT6A p.Pro994Ser (c.2980C>T)?

KAT6A p.Pro994Ser (c.2980C>T) is associated with autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome (ClinVar).

c.2980C>T · rs1564010191 · VCV2000579

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1307 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome

Computational evidence

Protein change
AlphaMissense	0.1307	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -5.48	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 2,019 bp · p 0.081 · regional, not allelic
Overall
CADD	23.9	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 0.00167% Admixed American · 1/59,908 alleles

Overall 0.000124% 2/1,611,852 alleles · very rare exomes 2/1,459,558 · genomes 0/152,294 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,908
European (non-Finnish)	8.48e-05%	1,178,752

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: KAT6A
Protein: p.Pro994Ser
Coding: c.2980C>T
MANE Select: NM_006766
dbSNP: rs1564010191
Type: single nucleotide variant
Location: chr8:41940901 (GRCh38)
Gene constraint: LOEUF 0.083 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.12 · 21 PDB
Residue 994: the 'disordered' region

Full KAT6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KAT6A p.Pro994= Benign ★★ same residue
KAT6A p.Pro994Leu Benign/Likely benign ★★ same residue
KAT6A p.Pro994Gln Benign ★ same residue
KAT6A p.Arg1012Ter Pathogenic ★★ same condition
KAT6A p.Arg1019Ter Pathogenic/Likely pathogenic ★★ same condition
KAT6A p.Arg1024Ter Pathogenic ★★ same condition
KAT6A p.Arg1129Ter Pathogenic ★★ same condition
KAT6A p.Arg220Ter 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/kat6a-p-pro994ser (accessed [today's date]).

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