Is SETBP1 p.His978= (c.2934C>T) pathogenic?

SETBP1 p.His978= (c.2934C>T) is classified Benign/Likely benign in SETBP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.049%, nfe); Associated with intellectual disability, autosomal dominant 29.

What condition is associated with SETBP1 p.His978= (c.2934C>T)?

SETBP1 p.His978= (c.2934C>T) is associated with intellectual disability, autosomal dominant 29, Schinzel-Giedion syndrome (ClinVar).

How common is SETBP1 p.His978= (c.2934C>T) in the general population?

SETBP1 p.His978= (c.2934C>T) is ultra-rare (popmax 0.049%, nfe) (gnomAD).

How is Non-specific syndromic intellectual disability inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SETBP1 p.His978=

c.2934C>T · rs145566816 · VCV546818

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.049%, nfe)

Conditions

intellectual disability, autosomal dominant 29

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -13	GERP -5.6
Overall
CADD	0.431	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.049% European (non-Finnish) · 578/1,180,032 alleles

Filtering AF 0.0457% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0443%

Overall 0.0405% 654/1,614,030 alleles · ultra-rare exomes 612/1,461,886 · genomes 42/152,144 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.049%	2,042
Admixed American	0.0483%	2,069
Remaining individualsnot grpmax-eligible	0.0336%	2,976
South Asian	0.0165%	6,071
East Asian	0.0111%	8,975
African / African-American	0.00534%	18,730
Finnishnot grpmax-eligible	0.00312%	32,021

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: SETBP1
Protein: p.His978=
Coding: c.2934C>T
MANE Select: NM_015559
dbSNP: rs145566816
Type: single nucleotide variant
Location: chr18:44952274 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30

Full SETBP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal dominant 29 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Schinzel-Giedion syndrome

For Non-specific syndromic intellectual disability (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood, Infancy

Similar variants

SETBP1 p.His978Asn Uncertain significance ★ ⚠ same residue
SETBP1 p.Arg530Ter Pathogenic ★★ same condition
SETBP1 p.Arg544Ter Pathogenic/Likely pathogenic ★★ same condition
SETBP1 p.Arg589Ter Pathogenic ★★ same condition
SETBP1 p.Arg625Ter Pathogenic ★★ same condition
SETBP1 p.Arg626Ter Pathogenic ★★ same condition
SETBP1 p.Asp868Asn Pathogenic ★★ ⚠ same condition
SETBP1 p.Asp868His 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/setbp1-p-his978 (accessed [today's date]).

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