Is SETD1A p.Pro531Ser (c.1591C>T) pathogenic?

SETD1A p.Pro531Ser (c.1591C>T) is classified Uncertain significance in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.082); Ultra-rare (popmax 0.0493%, mid); Associated with Inborn genetic diseases.

What condition is associated with SETD1A p.Pro531Ser (c.1591C>T)?

SETD1A p.Pro531Ser (c.1591C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1A p.Pro531Ser (c.1591C>T) in the general population?

SETD1A p.Pro531Ser (c.1591C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about SETD1A p.Pro531Ser (c.1591C>T)?

AlphaMissense predicts likely benign (score 0.082) — an in-silico prediction, not a clinical call.

SETD1A p.Pro531Ser

c.1591C>T · VCV3952787

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.082 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.082	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -6.13	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 981 bp · p 0.032 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00204% 33/1,614,048 alleles · ultra-rare exomes 32/1,461,840 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
European (non-Finnish)	0.00246%	40,691
Admixed American	0.00167%	60,008

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: SETD1A
Protein: p.Pro531Ser
Coding: c.1591C>T
MANE Select: NM_014712
Type: single nucleotide variant
Location: chr16:30965333 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 531: a UniProt-annotated variant site (in nedsid); the 'disordered' region

Full SETD1A 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

SETD1A p.Pro531Leu Uncertain significance ★ ⚠ same residue
SETD1A p.Ala671Thr Uncertain significance ★★ ⚠ same condition
SETD1A p.Ala840Val Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg1576Trp Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg276Trp Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg385His Uncertain significance ★★ ⚠ same condition
SETD1A p.Cys1638Phe Uncertain significance ★★ ⚠ same condition
SETD1A p.Glu1009Lys 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/setd1a-p-pro531ser (accessed [today's date]).

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