Is SETD1B p.Pro683Leu (c.2048C>T) pathogenic?

SETD1B p.Pro683Leu (c.2048C>T) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.1198); Very rare (popmax 0.00259%, eas); Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Pro683Leu (c.2048C>T)?

SETD1B p.Pro683Leu (c.2048C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Pro683Leu (c.2048C>T) in the general population?

SETD1B p.Pro683Leu (c.2048C>T) is very rare (popmax 0.00259%, eas) (gnomAD).

What do computational predictors say about SETD1B p.Pro683Leu (c.2048C>T)?

AlphaMissense predicts likely benign (score 0.1198) — an in-silico prediction, not a clinical call.

SETD1B p.Pro683Leu

c.2048C>T · rs1330809406 · VCV2275446

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1198 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00259%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1198	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -8.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,957 bp · p 0.61 · regional, not allelic
Overall
CADD	17.57	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 0.00259% East Asian · 1/38,654 alleles

Filtering AF 0.000575% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000454%

Overall 0.00101% 15/1,479,258 alleles · very rare exomes 13/1,338,620 · genomes 2/140,638 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00259%	38,654
African / African-American	0.00149%	67,154
South Asian	0.00124%	80,580
European (non-Finnish)	0.00108%	92,684

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.Pro683Leu
Coding: c.2048C>T
MANE Select: NM_001353345
dbSNP: rs1330809406
Type: single nucleotide variant
Location: chr12:121814263 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 683: 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-pro683leu (accessed [today's date]).

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