Is SETD1B p.Pro552Ser (c.1654C>T) pathogenic?

SETD1B p.Pro552Ser (c.1654C>T) is classified Likely benign in SETD1B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-25). AlphaMissense: likely benign (0.0928); Ultra-rare (popmax 0.0939%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Pro552Ser (c.1654C>T)?

SETD1B p.Pro552Ser (c.1654C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Pro552Ser (c.1654C>T) in the general population?

SETD1B p.Pro552Ser (c.1654C>T) is ultra-rare (popmax 0.0939%, nfe) (gnomAD).

What do computational predictors say about SETD1B p.Pro552Ser (c.1654C>T)?

AlphaMissense predicts likely benign (score 0.0928) — an in-silico prediction, not a clinical call.

SETD1B p.Pro552Ser

c.1654C>T · rs376158054 · VCV2351579

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0928 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0939%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0928	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,957 bp · p 0.61 · regional, not allelic
Overall
CADD	19.56	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 0.0939% European (non-Finnish) · 1,077/1,146,690 alleles

Filtering AF 0.0892% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0873%

Overall 0.0721% 1,117/1,548,526 alleles · ultra-rare exomes 1,059/1,396,202 · genomes 58/152,324 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0939%	1,065
Remaining individualsnot grpmax-eligible	0.0283%	3,535
African / African-American	0.0109%	9,147
Finnishnot grpmax-eligible	0.00876%	11,420
Admixed American	0.00784%	12,750
South Asian	0.00595%	16,806
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,644

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: SETD1B
Protein: p.Pro552Ser
Coding: c.1654C>T
MANE Select: NM_001353345
dbSNP: rs376158054
Type: single nucleotide variant
Location: chr12:121810599 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 552: the 'disordered' region

Full SETD1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD1B p.Ala1657Val Uncertain significance ★★ ⚠ same condition
SETD1B p.Ala654Thr Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1428Trp Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1458His Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1643His Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1670Gln Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg467Gln Uncertain significance ★★ ⚠ same condition
SETD1B p.Asp1107Asn Uncertain significance ★★ ⚠ 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/setd1b-p-pro552ser (accessed [today's date]).

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