Is SETD1B p.Pro438Leu (c.1313C>T) pathogenic?

SETD1B p.Pro438Leu (c.1313C>T) is classified Likely benign in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.1043); Ultra-rare (popmax 0.0342%, afr); Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Pro438Leu (c.1313C>T)?

SETD1B p.Pro438Leu (c.1313C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Pro438Leu (c.1313C>T) in the general population?

SETD1B p.Pro438Leu (c.1313C>T) is ultra-rare (popmax 0.0342%, afr) (gnomAD).

What do computational predictors say about SETD1B p.Pro438Leu (c.1313C>T)?

AlphaMissense predicts likely benign (score 0.1043) — an in-silico prediction, not a clinical call.

SETD1B p.Pro438Leu

c.1313C>T · rs991307899 · VCV3160603

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1043 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0342%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1043	likely benign
REVEL	0.361	indeterminate
SaProt	LLR -7.71	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 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 795 bp · p 0.65 · regional, not allelic
Overall
CADD	25.3	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 0.0342% African / African-American · 25/73,034 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0203%

Overall 0.00181% 28/1,545,714 alleles · ultra-rare exomes 10/1,393,546 · genomes 18/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0342%	2,921
Admixed American	0.00392%	25,486
Remaining individualsnot grpmax-eligible	0.00167%	60,038

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.Pro438Leu
Coding: c.1313C>T
MANE Select: NM_001353345
dbSNP: rs991307899
Type: single nucleotide variant
Location: chr12:121810258 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 438: 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-pro438leu (accessed [today's date]).

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