Is SETD1A p.Pro596Leu (c.1787C>T) pathogenic?

SETD1A p.Pro596Leu (c.1787C>T) is classified Likely benign in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.0696); Rare (popmax 0.111%, nfe).

How common is SETD1A p.Pro596Leu (c.1787C>T) in the general population?

SETD1A p.Pro596Leu (c.1787C>T) is rare (popmax 0.111%, nfe) (gnomAD).

What do computational predictors say about SETD1A p.Pro596Leu (c.1787C>T)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

SETD1A p.Pro596Leu

c.1787C>T · rs139187973 · VCV1711405

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.111%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR -8.80	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 3.7	GERP 1.1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 981 bp · p 0.032 · regional, not allelic
Overall
CADD	19.66	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 0.111% European (non-Finnish) · 1,314/1,178,912 alleles

Filtering AF 0.106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.104%

Overall 0.0981% 1,581/1,611,090 alleles · rare exomes 1,423/1,460,116 · genomes 158/150,974 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	4.55%	22
European (non-Finnish)grpmax	0.111%	897
Ashkenazi Jewishnot grpmax-eligible	0.0983%	1,017
Admixed American	0.0854%	1,171
Middle Eastern	0.0837%	1,195
South Asian	0.0792%	1,263
Remaining individualsnot grpmax-eligible	0.0785%	1,274
African / African-American	0.0174%	5,734
East Asian	0.0112%	8,945
Finnishnot grpmax-eligible	0.00315%	31,753

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro596Leu
Coding: c.1787C>T
MANE Select: NM_014712
dbSNP: rs139187973
Type: single nucleotide variant
Location: chr16:30965668 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 596: a UniProt-annotated variant site (in nedsid); the 'disordered' region

Full SETD1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETD1A p.Pro596Arg Uncertain significance ★★ ⚠ same residue
SETD1A p.Pro596= Likely benign ★ same residue
SETD1A c.518-2A>G Pathogenic ★★ same type
SETD1A p.Arg1571Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Arg176Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Arg668Ter Pathogenic ★★ same type
SETD1A p.Arg913Cys Likely pathogenic ★★ ⚠ same type
SETD1A p.Arg990Ter Pathogenic/Likely pathogenic ★★ 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/setd1a-p-pro596leu (accessed [today's date]).

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