Is SETD1B p.Val618Ala (c.1853T>C) pathogenic?

SETD1B p.Val618Ala (c.1853T>C) is classified Conflicting classifications of pathogenicity in SETD1B (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-26). AlphaMissense: likely benign (0.0501); Ultra-rare (popmax 0.0337%, mid); Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Val618Ala (c.1853T>C)?

SETD1B p.Val618Ala (c.1853T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Val618Ala (c.1853T>C) in the general population?

SETD1B p.Val618Ala (c.1853T>C) is ultra-rare (popmax 0.0337%, mid) (gnomAD).

What do computational predictors say about SETD1B p.Val618Ala (c.1853T>C)?

AlphaMissense predicts likely benign (score 0.0501) — an in-silico prediction, not a clinical call.

SETD1B p.Val618Ala

c.1853T>C · rs374027175 · VCV2643439

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0501 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0337%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0501	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -5.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP -0.55, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 3,957 bp · p 0.61 · regional, not allelic
Overall
CADD	11.18	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 0.0337% Middle Eastern · 2/5,926 alleles

Filtering AF 0.00814% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00757%

Overall 0.00744% 114/1,532,022 alleles · ultra-rare exomes 101/1,379,844 · genomes 13/152,178 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0337%	2,963
European (non-Finnish)	0.00961%	10,406
African / African-American	0.00276%	36,173
Remaining individualsnot grpmax-eligible	0.00169%	59,088

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.Val618Ala
Coding: c.1853T>C
MANE Select: NM_001353345
dbSNP: rs374027175
Type: single nucleotide variant
Location: chr12:121810798 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 618: 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.Val618Gly Uncertain significance ★★ ⚠ same residue
SETD1B p.Val618Leu Uncertain significance ★ ⚠ same residue
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

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-val618ala (accessed [today's date]).

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